Ppar agonists, compounds, pharmaceutical compositions, and methods of use thereof

ABSTRACT

Provided herein are compounds and compositions useful in increasing PPARδ activity. The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).

REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 17/162,157, filed Jan. 29, 2021, which is a continuation of U.S.application Ser. No. 16/682,676, filed Nov. 13, 2019 (now U.S. Pat. No.10,906,885), which is a continuation application of U.S. applicationSer. No. 16/510,976, filed Jul. 15, 2019 (now U.S. Pat. No. 10,479,775),which is a continuation application of U.S. application Ser. No.15/766,455, filed Apr. 6, 2018 (now U.S. Pat. No. 10,399,958); which isa U.S. national stage filing, under 35 U.S.C. § 371(c), of InternationalApplication No. PCT/US2016/055521, filed Oct. 5, 2016, which claims thebenefit of U.S. Provisional Application No. 62/238,629, filed Oct. 7,2015; U.S. Provisional Application No. 62/243,263, filed Oct. 19, 2015;and U.S. Provisional Application No. 62/352,348, filed Jun. 20, 2016.The entire contents of these applications are incorporated herein byreference.

FIELD

This application concerns agonists of peroxisome proliferator-activatedreceptors (PPAR), particularly PPAR delta (PPARδ), and methods for theiruse, such as to treat or prevent one or more PPARδ-related diseases.

BACKGROUND

Peroxisome proliferator-activated receptor delta (PPARδ) is a nuclearreceptor that is capable of regulating mitochondria biosynthesis. Asshown in PCT/2014/033088, incorporated herein by reference, modulatingthe activity of PPAR is useful for the treatment of diseases,developmental delays, and symptoms related to mitochondrial dysfunction,such as Alpers Disease, MERRF-Myoclonic epilepsy and ragged-red fiberdisease, Pearson Syndrome, and the like. Modulation PPAR activity iseffective in the treatment of other conditions, such as musculardiseases, demyelinating diseases, vascular diseases, and metabolicdiseases. Indeed, PPAR is an important biological target for compoundsused to help treat and prevent mitochondrial diseases, muscle-relateddiseases and disorders, and other related conditions.

Accordingly, there remains a need in the art for novel compounds capableof effectively and reliably activating PPARδ in vitro and in vivo. Thereis also a need for PPARδ activating compounds with improvedpharmacokinetic properties and improved metabolic stability. The presentinvention addresses these and other such needs.

SUMMARY

Provided herein, inter alia, are compounds and compositions comprisingsuch compounds that are useful for increasing PPARδ activity. Inparticular, disclosed herein are methods modulating the activity ofPPARδ for the treatment of diseases, developmental delays, and symptomsrelated to mitochondrial dysfunction (see, e.g., Example 1). Forexample, the disclosed compounds and compositions are useful in thetreatment of mitochondrial diseases, such as Alpers Disease,CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome(KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrialmyopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes,MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenicmuscle weakness, ataxia, and retinitis pigmentosa, and Pearson Syndrome.Alternatively, the disclosed compounds and compositions are useful inthe treatment of other PPARδ-related diseases, such as renal diseases,muscular diseases, demyelinating diseases, vascular diseases, andmetabolic diseases. For example, example 3 describes the use of Compound2d to improve mitochondrial biogenesis and function in Duchenne MuscularDystrophy (DMD) muscle cells. Example 4 describes the use of Compound 2dto increase capacity for endurance exercise in mouse model of DuchenneMuscular Dystrophy. Example 5 describes the use of Compound 2d to reducedystrophic muscle phenotype in mouse model of Duchenne MuscularDystrophy. Example 6 describes oral administration of Compounds 2a, 2d,and 2n to reduce ischemia-reperfusion induced kidney injury in rats.

In one embodiment, provided herein is a compound of Formula (I), (II),or (III):

or a pharmaceutically acceptable salt thereof,

wherein:

-   -   R¹ is hydrogen, halogen, —C₁-C₄-alkyl, —C₁-C₄-haloalkyl, —CN,        C₁-C₄-alkoxy, —C₁-C₄-haloalkoxy, or —C₃-C₆-cycloalkyl;    -   Q¹ is CH or N;    -   R² is hydrogen, halogen, —CN, —C₁-C₄-alkyl, —C₁-C₄-haloalkyl,        —C₃-C₆-cycloalkyl, —C₁-C₄-alkoxy, —C₁-C₄-haloalkoxy,        —S(C₁-C₄-alkyl), —SO₂(C₁-C₄-alkyl), 5- or 6-membered        heterocycle, aryl, 5-membered heteroaryl, —≡—R^(2A),        —O(CH₂)_(m)R^(2B), —NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, or        —C(O)(C₁-C₄-alkyl), wherein aryl and heteroaryl are optionally        substituted with halogen, —OH, —CN, —C₁-C₄-alkyl, formyl,        acetyl, acetoxy, or carboxy, and wherein m is an integer having        value of 1, 2, or 3;    -   x is an integer having a value of 1 or 2;    -   R^(2A) and R^(2B) are each independently —C₁-C₄-alkyl,        —C₁-C₄-haloalkyl, or —C₃-C₆-cycloalkyl;    -   each R²⁰ is independently hydrogen, halogen, —C₁-C₄-alkyl, —CN,        or —C₁-C₄-alkoxy; and    -   R³ is —CH₃ or —CD₃.

Pharmaceutical compositions of compounds of Formula (I), (II), and (III)also are disclosed herein. Particular embodiments comprise apharmaceutically acceptable carrier or excipient and one or more of thedisclosed compounds, or a pharmaceutically acceptable salt thereof. Thepharmaceutical compositions of the invention can be used in therapy,e.g., for treating a PPARδ-related disease or condition in a subject.

Another embodiment comprises treating a PPARδ-related disease orcondition in a subject by administering to the subject a therapeuticallyeffective amount of one or more disclosed compounds, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound(s).

Also provided herein is the use of one or more of the disclosedcompounds, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising one or more of the disclosedcompounds, for the preparation of a medicament for the treatment of aPPARδ-related disease or condition.

In another embodiment, provided herein the disclosed compounds, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising one or more of the disclosed compounds are foruse in treating a PPARδ-related disease or condition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing fatty acid oxidation increases with Compound2d administration in Duchenne Muscular Dystrophy (DMD) patient cells.

FIG. 2 is a graph showing mitochondrial biogenesis increases withCompound 2d treatment in DMD patient cells.

FIG. 3 is a graph showing treadmill running distance of DMD model mouse(mdx) increases with Compound 2d.

FIG. 4 is a plot showing pathology scored necrosis is reduced in mdxquadriceps with Compound 2d treatment.

FIG. 5 is a graph showing necrotic region size is decreased withCompound 2d administration in mdx mice.

FIG. 6 is a plot showing inflammation is reduced in mdx quadricepsmuscle with Compound 2d administration.

FIG. 7 is a plot showing quadriceps muscle regeneration is increasedwith Compound 2d administration in mdx mice.

FIG. 8 is a graph showing diaphragm muscle necrosis is reduced withCompound 2d administration in mdx mice.

FIG. 9 is a graph showing mdx diaphragm muscles are more fibrotic thanhealthy, non-dystropic control mouse diaphragms.

FIG. 10 is a graph showing Compound 2d administration reduces mdx mousediaphragm fibrosis.

FIG. 11A is a graph showing the therapeutic effect of oraladministration of Compound 2a in a rat model of acute kidney injury.FIG. 11B is a graph showing the therapeutic effect of oraladministration of Compound 2d in a rat model of acute kidney injury.FIG. 11C is a graph showing the therapeutic effect of oraladministration of Compound 2n in a rat model of acute kidney injury.

DETAILED DESCRIPTION

Peroxisome proliferator-activated receptor delta (PPAR-δ), also known asperoxisome proliferator-activated receptor beta (PPAR-β) or as NR1C2(nuclear receptor subfamily 1, group C, member 2), refers to a nuclearreceptor protein that function as a transcription factor regulating theexpression of genes. Ligands of PPARδ can promote myoblast proliferationafter injury, such as injury to skeletal muscle. PPARδ (OMIM 600409)sequences are publically available, for example from GenBank® sequencedatabase (e.g., accession numbers NP 001165289.1 (human, protein) NP035275 (mouse, protein), NM 001171818 (human, nucleic acid) and NM011145 (mouse, nucleic acid)).

Herein, the phrase “PPARδ agonist” refers to substances that increasethe activity of PPARδ. Substances can be tested for their PPARδ agonistactivity by contacting the substance with cells expressing PPARδ,detecting their binding with PPARδ and then detecting signals that serveas the indicator of the activation of PPARδ.

Definitions

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy”, “haloalkyl”, “haloalkoxy”, “cycloalkyl”, and the like, meanssaturated aliphatic straight-chain or branched monovalent hydrocarbonradical. Unless otherwise specified, an alkyl group typically has 1 to 4carbon atoms, i.e., C₁-C₄-alkyl. As used herein, a “C₁-C₄-alkyl” groupmeans a radical having from 1 to 4 carbon atoms in a linear or branchedarrangement, and includes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom,represented by —O-alkyl. For example, “C₁-C₄-alkoxy” includes methoxy,ethoxy, propoxy, isopropoxy and butoxy.

The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, as the casemay be, substituted with one or more halogen atoms. For example,“C₁-C₄-haloalkyl” includes fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, fluoroethyl,difluoroethyl, dichloroethyl and chloropropyl, and “C₁-C₄-haloalkoxy”includes fluoromethoxy, difluoromethoxy, trifluoromethoxy,chloromethoxy, dichloromethoxy, bromomethoxy, fluoroethoxy,difluoroethoxy, dichloroethoxy and chloropropoxy.

The term “halogen” means fluorine or fluoro (F), chlorine or chloro(Cl), bromine or bromo (Br), or iodine or iodo (I).

Examples of “aryl” include phenyl, naphthyl, anthracenyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl andindenyl.

“Cycloalkyl” means a 3-12 membered saturated aliphatic cyclichydrocarbon radical. It can be monocyclic, bicyclic (e.g., a bridged orfused bicyclic ring), or tricyclic. For example, monocyclicC₃-C₆-cycloalkyl means a radical having from 3 to 6 carbon atomsarranged in a monocyclic ring. For example, “C₃-C₆-cycloalkyl” includes,but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

“5- or 6-membered heterocycle” means a radical having from 5 or 6 ringatoms (including 1 to 3 ring heteroatoms) arranged in a monocyclic ring.Examples of “5- or 6-membered heterocycle” include, but are not limitedto, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, dihydroimidazole,dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl,dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl,tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, and tetrahydrothiopyranyl.

“5-membered heteroaryl” means a monocyclic aromatic ring system havingfive ring atoms selected from carbon and at least one (typically 1 to 3,more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur).Typical examples are 5-membered heteroaryl containing 1 or 2 atomsselected independently from nitrogen atoms, sulfur atoms and oxygenatoms such as pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, and the like.

If a group is described as being “substituted”, a non-hydrogensubstituent is in the place of hydrogen on a carbon, sulfur or nitrogenof the substituent. Thus, for example, a substituted alkyl is an alkylwherein at least one non-hydrogen substituent is in the place ofhydrogen on the alkyl substituent. To illustrate, monofluoroalkyl isalkyl substituted with a fluoro substituent, and difluoroalkyl is alkylsubstituted with two fluoro substituents. It should be recognized thatif there is more than one substitution on a substituent, eachnon-hydrogen substituent can be identical or different (unless otherwisestated). A person of ordinary skill in the art will recognize that thecompounds and definitions provided do not include impermissiblesubstituent patterns (e.g., methyl substituted with 5 different groups,and the like) Such impermissible substitution patterns are clearlyrecognized by a person of ordinary skill in the art.

Compounds having one or more chiral centers can exist in variousstereoisomeric forms. Stereoisomers are compounds that differ only intheir spatial arrangement. Stereoisomers include all diastereomeric,enantiomeric, and epimeric forms as well as racemates and mixturesthereof. The term “geometric isomer” refers to compounds having at leastone double bond, wherein the double bond(s) may exist in cis, trans syn,anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof.When a disclosed compound is named or depicted by structure withoutindicating stereochemistry, it is understood that the name or thestructure encompasses one or more of the possible stereoisomers, orgeometric isomers, or a mixture of the encompassed stereoisomers orgeometric isomers.

When a geometric isomer is depicted by name or structure, it is to beunderstood that the geometric isomeric purity of the named or depictedgeometric isomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure byweight. Geometric isomeric purity is determined by dividing the weightof the named or depicted geometric isomer in the mixture by the totalweight of all of the geometric isomers in the mixture.

Racemic mixture means 50% of one enantiomer and 50% of is correspondingenantiomer. When a compound with one chiral center is named or depictedwithout indicating the stereochemistry of the chiral center, it isunderstood that the name or structure encompasses both possibleenantiomeric forms (e.g., both enantiomerically-pure,enantiomerically-enriched or racemic) of the compound. When a compoundwith two or more chiral centers is named or depicted without indicatingthe stereochemistry of the chiral centers, it is understood that thename or structure encompasses all possible diasteriomeric forms (e.g.,diastereomerically pure, diastereomerically enriched and equimolarmixtures of one or more diastereomers (e.g., racemic mixtures) of thecompound.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well-known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers also can be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers are included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers isat least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomericpurity in this case is determined by dividing the total weight in themixture of the stereoisomers encompassed by the name or structure by thetotal weight in the mixture of all of the stereoisomers.

Included in the present teachings are pharmaceutically acceptable saltsof the compounds disclosed herein. The disclosed compounds have basicamine groups and therefore can form pharmaceutically acceptable saltswith pharmaceutically acceptable acid(s). Suitable pharmaceuticallyacceptable acid addition salts of the compounds described herein includesalts of inorganic acids (such as hydrochloric acid, hydrobromic,phosphoric, nitric, and sulfuric acids) and of organic acids (such as,e.g., acetic acid, benzenesulfonic, benzoic, methanesulfonic, andp-toluenesulfonic acids). For example, in one embodiment the acidaddition salt is a hemisulfate salt. Compounds of the present teachingswith acidic groups such as carboxylic acids can form pharmaceuticallyacceptable salts with pharmaceutically acceptable base(s). Suitablepharmaceutically acceptable basic salts include ammonium salts, alkalimetal salts (such as sodium and potassium salts), alkaline earth metalsalts (such as magnesium and calcium salts) and organic base salts (suchas meglumine salt).

As used herein, the term “pharmaceutically-acceptable salt” refers topharmaceutical salts that are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, and allergic response,and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically-acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describes pharmacologically acceptablesalts in J. Pharm. Sci., 1977, 66:1-19.

The neutral forms of the compounds of the invention are regenerated fromtheir corresponding salts by contacting the salt with a base or acid andisolating the parent compound in the conventional manner. The parentform of the compound may differ from the various salt forms in certainphysical properties, such as solubility in polar solvents. The neutralforms of compounds disclosed herein also are included in the invention.

The terms “administer”, “administering”, “administration”, and the like,as used herein, refer to methods that may be used to enable delivery ofcompositions to the desired site of biological action. These methodsinclude, but are not limited to, intraarticular (in the joints),intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, orally, topically, intrathecally, inhalationally,transdermally, rectally, and the like. Administration techniques thatcan be employed with the agents and methods described herein are foundin e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

As used herein, the terms “co-administration”, “administered incombination with”, and their grammatical equivalents, are meant toencompass administration of two or more therapeutic agents to a singlesubject, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments the one or morecompounds described herein will be co-administered with other agents.These terms encompass administration of two or more agents to thesubject so that both agents and/or their metabolites are present in thesubject at the same time. They include simultaneous administration inseparate compositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. Thus, in some embodiments, the compounds describedherein and the other agent(s) are administered in a single composition.In some embodiments, the compounds described herein and the otheragent(s) are admixed in the composition.

Generally, an effective amount of a compound taught herein variesdepending upon various factors, such as the given drug or compound, thepharmaceutical formulation, the route of administration, the type ofdisease or disorder, the identity of the subject or host being treated,and the like, but can nevertheless be routinely determined by oneskilled in the art. An effective amount of a compound of the presentteachings may be readily determined by one of ordinary skill by routinemethods known in the art.

The term “effective amount” or “therapeutically effective amount” meansan amount when administered to the subject which results in beneficialor desired results, including clinical results, e.g., inhibits,suppresses or reduces the symptoms of the condition being treated in thesubject as compared to a control. For example, a therapeuticallyeffective amount can be given in unit dosage form (e.g., from 1 mg toabout 50 g per day, e.g., from 1 mg to about 5 grams per day).

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g., the subject, the disease, the disease state involved,the particular treatment, and whether the treatment is prophylactic).Treatment can involve daily or multi-daily or less than daily (such asweekly or monthly etc.) doses over a period of a few days to months, oreven years. However, a person of ordinary skill in the art wouldimmediately recognize appropriate and/or equivalent doses looking atdosages of approved compositions for treating a PPARδ related diseaseusing the disclosed PPAR agonists for guidance.

A “subject” is a mammal, preferably a human, but can also be an animalin need of veterinary treatment, e.g., companion animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, andthe like) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the compositions of the present disclosure withoutcausing a significant adverse toxicological effect on the subject.

Non-limiting examples of pharmaceutically acceptable carriers andexcipients include water, NaCl, normal saline solutions, lactatedRinger's, normal sucrose, normal glucose, binders, fillers,disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions(such as Ringer's solution), alcohols, oils, gelatins, carbohydratessuch as lactose, amylose or starch, fatty acid esters,hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.Such preparations can be sterilized and, if desired, mixed withauxiliary agents such as lubricants, preservatives, stabilizers, wettingagents, emulsifiers, salts for influencing osmotic pressure, buffers,coloring, and/or aromatic substances and the like that do notdeleteriously react with or interfere with the activity of the compoundsprovided herein. One of ordinary skill in the art will recognize thatother pharmaceutical carriers and excipients are suitable for use withdisclosed compounds.

Compounds of the Invention

Disclosed herein are embodiments of a compound having general Formula(I), (II), or

or a pharmaceutically acceptable salt thereof,

wherein:

-   -   R¹ is hydrogen, halogen, —C₁-C₄-alkyl, —C₁-C₄-haloalkyl, —CN,        —C₁-C₄-alkoxy, —C₁-C₄-haloalkoxy, or —C₃-C₆-cycloalkyl;    -   Q¹ is CH or N;    -   R² is hydrogen, halogen, —CN, —C₁-C₄-alkyl, —C₁-C₄-haloalkyl,        —C₃-C₆-cycloalkyl, alkoxy, —C₁-C₄-haloalkoxy, —SO₂(C₁-C₄-alkyl),        5- or 6-membered heterocycle, aryl, 5-membered heteroaryl,        —O(CH₂)_(m)R^(2B), —NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, or        —C(O)(C₁-C₄-alkyl), wherein aryl and heteroaryl are optionally        substituted with halogen, —OH, —CN, formyl, acetyl, acetoxy, or        carboxy, and wherein m is an integer having value of 1, 2, or 3;    -   x is an integer having a value of 1 or 2;    -   R^(2A) and R^(2B) are each independently —C₁-C₄-alkyl,        —C₁-C₄-haloalkyl, or —C₃-C₆-cycloalkyl; each R²⁰ is        independently hydrogen, halogen, —C₁-C₄-alkyl, —CN, or        —C₁-C₄-alkoxy; and    -   R³ is CH₃ or CD₃.

In a 1^(st) embodiment, the compound has the structure of Formula (I),(II), or (III), wherein R³ is CH₃, and the remaining variables are thesame as defined above.

In a 2^(nd) embodiment, the compound has the structure of Formula (Ia),(IIa), or (IIIa):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined for Formulas (I), (II), and (III).

In a 3^(rd) embodiment, the compound the compound has the structure ofFormula (Iaa):

or, alternatively, the structure of Formula (Iaa′):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the 1^(st) embodiment.

In a 4^(th) embodiment, the compound has the structure of Formula (Ib),(IIb) or (IIIb):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the 1^(st) embodiment.

In a 5^(th) embodiment, the compound the compound has the structure ofFormula (Ibb):

or, alternatively, the structure of Formula (Ibb′):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the 1^(st) embodiment.

In a 6^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR² is halogen, —C₁-C₄-alkyl, —C₁-C₄-haloalkyl, —C₁-C₄-haloalkoxy,—S(C₁-C₄-alkyl), or furanyl, wherein the furanyl can be optionallysubstituted with —C₁-C₄-alkyl; and the remainder of the variables are asdefined in the 1^(st) embodiment.

In a 7^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR² is halogen, —CH₃, —C₁-haloalkyl, —C₁-haloalkoxy, —SCH₃, or furanyl,wherein the furanyl can be optionally substituted with —CH₃; and theremainder of the variables are as defined in the 1^(st) embodiment.

In a 8^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR² is halogen, —CH₃, —C₁-haloalkyl, —C₁-haloalkoxy, or —SCH₃, and theremainder of the variables are as defined in the 1^(st) embodiment.

In an 9^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR² is chloro, unsubstituted furanyl, —CH₃, —CF₃, —OCF₃, —OCHF₂, or—SCH₃, and the remainder of the variables are as defined in the 1^(st)embodiment.

In a 10^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR² is —CF₃ or —OCF₃, and the remainder of the variables are as definedin the 1^(st) embodiment.

In an 11^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR² is —CF₃, and the remainder of the variables are as defined in the1^(st) embodiment.

In a 12^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR¹ is hydrogen or halogen; and the remainder of the variables are asdefined in the 1^(st), 6^(th), 7^(th), 8^(th), 9^(th), 10^(th), or11^(th) embodiment.

In a 13^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR¹ is hydrogen or fluoro; and the remainder of the variables are asdefined in the 1^(st), 6^(th), 7^(th), 8^(th), 9^(th), 10^(th), or11^(th) embodiment.

In a 14^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereineach R²⁰ is independently hydrogen or halogen; and the remainder of thevariables are as defined in the 1^(st), 6^(th), 7^(th), 8^(th), 9^(th),10^(th), 11^(th), 12^(th), or 13^(th) embodiment.

In a 15^(th) embodiment, the compound has the structure of any one ofFormulas (I)-(III), (Ia)-(IIIa), (Iaa), (Ib)-(IIIb), or (Ibb), whereinR²⁰ is hydrogen or fluoro; and the remainder of the variables are asdefined in the 1^(st), 6^(th), 7^(th), 8^(th), 9^(th), 10^(th), 11^(th),12^(th), or 13^(th) embodiment.

In a 16^(th) embodiment, the compound has the structure of any one ofFormula (Iaa) or (Ibb), wherein R¹ is hydrogen or fluoro, R² isC₁-C₄-haloalkyl or C₁-C₄-haloalkoxy, R²⁰ is hydrogen, and x is aninteger having a value of 1.

In a 17^(th) embodiment, the compound has the structure of any one ofFormula (Iaa) or (Ibb), wherein R¹ is hydrogen, R² is trifluoromethyl ortrifluoromethoxy, R²⁰ is hydrogen, and x is an integer having a value of1.

In certain embodiments, the invention is any one of the compoundsdepicted in the exemplification section of the instant application;pharmaceutically acceptable salts as well as the neutral forms of thesecompounds also are included in the invention. Specifically, disclosedembodiments concern is any one of the compounds depicted in Examples2a-2u; pharmaceutically acceptable salts as well as the neutral forms ofthese compounds also are included in the disclosed embodiments. Inpreferred embodiments, disclosed embodiments concern any one ofCompounds 2a-2u; pharmaceutically acceptable salts as well as theneutral forms of these compounds also are included in the disclosedembodiments.

Another embodiment of the invention is hydrates or other solvates of thecompounds disclosed herein, such as ethanolates, and crystal polymorphsubstances of any one of the compound of the formula (I), (II) and (III)or a pharmaceutically acceptable salt thereof.

Methods of Preparing Compounds of the Invention

Methods of preparing compounds of Formula (I), (II), and (III) aredisclosed. In general, a compound of Formula (I), wherein R³ is —CH₃,may be prepared by reacting a compound of Formula (IV)

with prop-2-yn-1amine to afford a compound of Formula (V):

The compound of Formula (V) can be subsequently reacted with2-methoxybenzylamine to afford a compound of Formula (VI):

The compound of Formula (IV) then can be subjected to demethylationconditions to afford a compound of Formula (VII):

The compound of Formula (VII) can be reacted with (R)-ethyl6-bromo-3-methylhexanoate to afford a compound of formula (VIII):

Subsequently, the compound of Formula (VII) may be subjected tohydrolysis conditions to afford the compound of Formula (I).

Similarly, a compound of Formula (II) may be prepared by reacting acompound of Formula (VII) with (E)-ethyl 6-bromo-4-methylhex-4-enoate toafford a compound of Formula (IX):

Subsequent hydrolysis of the compound of Formula (IX) affords thecompound of Formula (II).

Likewise, a compound of Formula (III) may be prepared by reacting acompound of Formula (VII) with (E)-ethyl6-bromo-2,2-dimethylhex-4-enoate to afford a compound of Formula (X):

Subsequent hydrolysis of the compound of Formula (X) affords thecompound of Formula (III).

Detailed synthetic protocols for preparing exemplary compounds ofFormula (I), (II), and (III) are presented in Examples 2a-2u.

Methods of Treatment

Methods of treating a PPARδ-related disease or condition in a subjectare disclosed. The methods can include administering to the subject atherapeutically effective amount of one or more compounds orcompositions provided herein.

In one embodiment, the PPARδ-related disease is a mitochondrial disease.Examples of mitochondrial diseases include, but are not limited to,Alpers Disease, CPEO-Chronic progressive external ophthalmoplegia,Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON),MELAS-Mitochondrial myopathy, encephalomyopathy, lactic acidosis, andstroke-like episodes, MERRF-Myoclonic epilepsy and ragged-red fiberdisease, NARP-neurogenic muscle weakness, ataxia, and retinitispigmentosa, and Pearson Syndrome.

In other embodiments, the PPARδ-related disease is a vascular disease(such as a cardiovascular disease or any disease that would benefit fromincreasing vascularization in tissues exhibiting impaired or inadequateblood flow). In other embodiments, the PPARδ-related disease is amuscular disease, such as a muscular dystrophy. Examples of musculardystrophy include but are not limited to Duchenne muscular dystrophy,Becker muscular dystrophy, limb-girdle muscular dystrophy, congenitalmuscular dystrophy, facioscapulohumeral muscular dystrophy, myotonicmuscular dystrophy, oculopharyngeal muscular dystrophy, distal musculardystrophy, and Emery-Dreifuss muscular dystrophy.

In some embodiments, the PPARδ-related disease or condition is ademyelinating disease, such as multiple sclerosis, Charcot-Marie-Toothdisease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitisoptica, adrenoleukodystrophy, or Guillian-Barre syndrome.

In other embodiments, the PPARδ-related disease is a metabolic disease.Examples of metabolic diseases include but are not limited to obesity,hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia,hypercholesterolemia, dyslipidemia, Syndrome X, and Type II diabetesmellitus.

In yet other embodiments, the PPARδ-related disease is a musclestructure disorder. Examples of a muscle structure disorders include,but are not limited to, Bethlem myopathy, central core disease,congenital fiber type disproportion, distal muscular dystrophy (MD),Duchenne & Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyalinebody myopathy, limb-girdle MD, a muscle sodium channel disorders,myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy,nemaline body disease, oculopharyngeal MD, and stress urinaryincontinence.

In still other embodiments, the PPARδ-related disease is a neuronalactivation disorder, Examples of neuronal activation disorders include,but are not limited to, amyotrophic lateral sclerosis,Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eatonsyndrome, multiple sclerosis, myasthenia gravis, nerve lesion,peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy,and toxic myoneural disorder.

In other embodiments, the PPARδ-related disease is a muscle fatiguedisorder. Examples of muscle fatigue disorders include, but are notlimited to chronic fatigue syndrome, diabetes (type I or II), glycogenstorage disease, fibromyalgia, Friedreich's ataxia, intermittentclaudication, lipid storage myopathy, MELAS, mucopolysaccharidosis,Pompe disease, and thyrotoxic myopathy.

In some embodiments, the PPARδ-related disease is a muscle massdisorder. Examples of muscle mass disorders include, but are not limitedto, cachexia, cartilage degeneration, cerebral palsy, compartmentsyndrome, critical illness myopathy, inclusion body myositis, muscularatrophy (disuse), sarcopenia, steroid myopathy, and systemic lupuserythematosus.

In other embodiments, the PPARδ-related disease is a beta oxidationdisease. Examples of beta oxidation diseases include, but are notlimited to, systemic carnitine transporter, carnitinepalmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoAdehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzymedeficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency,short-chain acyl-CoA dehydrogenase (SCAD) deficiency, andriboflavin-responsive disorders of β-oxidation (RR-MADD).

In some embodiments, the PPARδ-related disease is a vascular disease.Examples of vascular diseases include, but are not limited to,peripheral vascular insufficiency, peripheral vascular disease,intermittent claudication, peripheral vascular disease (PVD), peripheralartery disease (PAD), peripheral artery occlusive disease (PAOD), andperipheral obliterative arteriopathy.

In other embodiments, the PPARδ-related disease is an ocular vasculardisease. Examples of ocular vascular diseases include, but are notlimited to, age-related macular degeneration (AMD), stargardt disease,hypertensive retinopathy, diabetic retinopathy, retinopathy, maculardegeneration, retinal haemorrhage, and glaucoma.

In yet other embodiments, the PPARδ-related disease is a muscular eyedisease. Examples of muscular eye diseases include, but are not limitedto, strabismus (crossed eye/wandering eye/walleye ophthalmoparesis),progressive external ophthalmoplegia, esotropia, exotropia, a disorderof refraction and accommodation, hypermetropia, myopia, astigmatism,anisometropia, presbyopia, a disorders of accommodation, or internalophthalmoplegia.

In yet other embodiments, the PPARδ-related disease is a metabolicdisease. Examples of metabolic disorders include, but are not limitedto, hyperlipidemia, dyslipidemia, hyperchlolesterolemia,hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemiaand/or HLD non-cholesterolemia, VLDL hyperproteinemia,dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis,disease of arterial sclerosis, disease of cardiovascular systems,cerebrovascular disease, peripheral circulatory disease, metabolicsyndrome, syndrome X, obesity, diabetes (type I or II), hyperglycemia,insulin resistance, impaired glucose tolerance, hyperinsulinism,diabetic complication, cardiac insufficiency, cardiac infarction,cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD),nonalcoholic steatohepatitis (NASH), thrombus, Alzheimer disease,neurodegenerative disease, demyelinating disease, multiple sclerosis,adrenal leukodystrophy, dermatitis, psoriasis, acne, skin aging,trichosis, inflammation, arthritis, asthma, hypersensitive intestinesyndrome, ulcerative colitis, Crohn's disease, and pancreatitis.

In still other embodiments, the PPARδ-related disease is cancer.Examples of cancer include, but are not limited to, cancers of thecolon, large intestine, skin, breast, prostate, ovary, and/or lung.

In other embodiments, the PPARδ-related disease is an ischemic injury.Examples of ischemic injuries include, but are not limited to, cardiacischemia, such as myocardial infarction; brain ischemia (e.g., acuteischemic stroke; chronic ischemic of the brain, such as vasculardementia; and transient ischemic attack (TIA); bowel ischemia, such asischemic colitis; limb ischemia, such as acute arm or leg ischemia;subcutaneous ischemia, such as cyanosis or gangrene; and ischemic organinjury, such as ischemic renal injury (IRI).

In still other embodiments, the PPARδ-related disease is a renaldisease. Examples of renal diseases include, but are not limited to,glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, acute nephritis, recurrent hematuria, persistenthematuria, chronic nephritis, rapidly progressive nephritis, acutekidney injury (also known as acute renal failure), chronic renalfailure, diabetic nephropathy, or Bartter's syndrome. PCT/US2014/033088,incorporated herein by reference, demonstrates genetic andpharmacological activation of PPARδ promotes muscle regeneration in anacute thermal injury mouse model. Accordingly, use of PPARδ as atherapeutic target to enhance regenerative efficiency of skeletal muscleis also provided.

Pharmaceutical Compositions and Administration Thereof

Additional Therapeutic Agents

Pharmaceutical compositions are disclosed that include one or morecompounds provided herein (such as 1, 2, 3, 4, or 5 of such compounds),and typically at least one additional substance, such as an excipient, aknown therapeutic other than those of the present disclosure, andcombinations thereof. In some embodiments, the disclosed PPAR agonistscan be used in combination with other agents known to have beneficialactivity with the disclosed PPAR agonists. For example, disclosedcompounds can be administered alone or in combination with one or moreother PPAR agonists, such as a thiazolidinedione, includingrosiglitazone, pioglitazone, troglitazone, and combinations thereof, ora sulfonylurea agent or a pharmaceutically acceptable salt thereof, suchas tolbutamide, tolazamide, glipizide, carbutamide, glisoxepide,glisentide, glibornuride, glibenclamide, gliquidone glimepiride,gliclazide and the pharmaceutically acceptable salts of these compounds,or muraglitazar, farglitazar, naveglitazar, netoglitazone,rivoglitazone, K-111, GW-677954, (−)-Halofenate, acid, arachidonic acid,clofbrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate,lovastatin, pravastatin, simvastatin, mevastatin, fluvastatin,indomethacin, fenoprofen, ibuprofen, and the pharmaceutically acceptablesalts of these compounds.

In one embodiment, disclosed compounds may be administered incombination with dexamphetamine, amphetamine, mazindole or phentermine;and administered in combination with medicaments having ananti-inflammatory effect.

Further, when used for the treatment of a metabolic condition, thepharmaceutical compositions provided herein can be administered as acombination therapy with one or more pharmacologically active substanceshaving favorable effects on metabolic disturbances or disorders. Forexample, the disclosed pharmaceutical compositions may be administeredin combination with RXR agonists for treating metabolic andcardiovascular diseases medicaments, which lower blood glucose;antidiabetics, such as insulins and insulin derivatives, includingLantus, Apidra, and other fast-acting insulins, and GLP-1 receptormodulators; active ingredients for treating dyslipidemias;anti-atherosclerotic medicaments; anti-obesity agents; anti-inflammatoryactive ingredients; active ingredients for treating malignant tumors;anti-thrombotic active ingredients; active ingredients for treating highblood pressure; active ingredients for treating heart failure, andcombinations thereof.

Methods of Administration

The precise amount of compound administered to provide a therapeuticallyeffective amount to the subject will depend on the mode ofadministration, the type, and severity of the the disease and/orcondition and on the characteristics of the subject, such as generalhealth, age, sex, body weight, and tolerance to drugs. One of ordinaryskill in the art will be able to determine appropriate dosages dependingon these and other factors. When administered in combination with othertherapeutic agents, a “therapeutically effective amount” of anyadditional therapeutic agent(s) will depend on the type of drug used.Suitable dosages are known for approved therapeutic agents and can beadjusted by one of ordinary skill in the art according to the conditionof the subject, the type of condition(s) being treated and the amount ofa compound of the invention being used by following, for example,dosages reported in the literature and recommended in the Physician'sDesk Reference (57th ed., 2003). For example, a therapeuticallyeffective amount can be given in unit dosage form (e.g., 0.1 mg to about50 g per day).

The disclosed PPARδ agonists can be administered to a subject by routesknown to one of skill in the art. Examples of routes of administrationinclude, but are not limited to, parenteral, e.g., intravenous,intradermal, subcutaneous, oral, intranasal (e.g., inhalation),transdermal, topical, transmucosal, and rectal administration. Anexemplary method for oral administration of the compounds of theinvention is shown for Compound 2a, Compound 2d, and Compound 2n herein(see Example 6). Exemplary methods for intravenous administration of thecompounds of the invention is described in U.S. Provisional ApplicationNo. 62/404,390, incorporated herein by reference.

Administration of therapeutic agents by intravenous formulation is wellknown in the pharmaceutical industry. Intravenous formulations comprisethe pharmaceutically active agent dissolved in a pharmaceuticallyacceptable solvent or solution, such as sterile water, normal salinesolutions, lactated Ringer's, or other salt solutions such as Ringer'ssolution.

An oral formulation typically is prepared as a compressed preparationin, for example, the form of a tablet or pill. A tablet may contain, forexample, about 5-10% of the active ingredient (e.g., a salt of Formula(I), (II), or (III)); about 80% of fillers, disintegrants, lubricants,glidants, and binders; and 10% of compounds which ensure easydisintegration, disaggregation, and dissolution of the tablet in thestomach or the intestine. Pills can be coated with sugar, varnish, orwax to disguise the taste.

EXEMPLIFICATION Example 1a PPARδ Activity Screen

Cell Culture and Transfection: CV-1 cells were grown in DMEM+10%charcoal stripped FCS. Cells were seeded into 384-well plates the daybefore transfection to give a confluency of 50-80% at transfection. Atotal of 0.8 g DNA containing 0.64 micrograms pCMX-PPARDelta LBD, 0.1micrograms pCMX.beta.Gal, 0.08 micrograms pGLMH2004 reporter and 0.02micrograms pCMX empty vector was transfected per well using FuGenetransfection reagent according to the manufacturer's instructions(Roche). Cells were allowed to express protein for 48 h followed byaddition of compound.

Plasmids: Human PPARδ was used to PCR amplify the PPARδ LBD. Theamplified cDNA ligand binding domain (LBD) of PPARδ isoform was (PPARδamino acid 128 to C-terminus) and fused to the DNA binding domain (DBD)of the yeast transcription factor GAL4 by subcloning fragments in frameinto the vector pCMX GAL (Sadowski et al. (1992), Gene 118, 137)generating the plasmids pCMX-PPARDelta LBD. Ensuing fusions wereverified by sequencing. The pCMXMH2004 luciferase reporter containsmultiple copies of the GAL4 DNA response element under a minimaleukaryotic promoter (Hollenberg and Evans, 1988). pCMXPGal wasgenerated.

Compounds: All compounds were dissolved in DMSO and diluted 1:1000 uponaddition to the cells. Compounds were tested in quadruple inconcentrations ranging from 0.001 to 100 μM. Cells were treated withcompound for 24 h followed by luciferase assay. Each compound was testedin at least two separate experiments.

Luciferase assay: Medium including test compound was aspirated andwashed with PBS. 50 μl PBS including 1 mM Mg++ and Ca++ were then addedto each well. The luciferase assay was performed using the LucLite kitaccording to the manufacturer's instructions (Packard Instruments).Light emission was quantified by counting on a Perkin Elmer Envisionreader. To measure 3-galactosidase activity 25 μl supernatant from eachtransfection lysate was transferred to a new 384 microplate.Beta-galactosidase assays were performed in the microwell plates using akit from Promega and read in a Perkin Elmer Envision reader. Thebeta-galactosidase data were used to normalize (transfection efficiency,cell growth etc.) the luciferase data.

Statistical Methods: The activity of a compound is calculated as foldinduction compared to an untreated sample. For each compound theefficacy (maximal activity) is given as a relative activity compared toGW501516, a PPARδ agonist. The EC₅₀ is the concentration giving 50% ofmaximal observed activity. EC₅₀ values were calculated via non-linearregression using GraphPad PRISM (GraphPad Software, San Diego, Calif).

TABLE 1 PPARdelta Activity Screen PPAR delta Mol. transactivationCompound Structure Wt EC50 (nM) Compound 2a

476.50 1.00 Compound 2b

426.93 7.80 Compound 2c

458.54 3.70 Compound 2d

460.41 0.10 Compound 2e

474.47 0.20 Compound 2f

406.52 24.30 Compound 2g

410.48 39.00 Compound 2h

492.50 3.50 Compound 2i

458.95 18.80 Compound 2j

444.93 0.80 Compound 2k

478.47 6.60 Compound 2l

458.50 13.50 Compound 2m

490.51 0.50 Compound 2n

461.49 4.40 Compound 2o

442.50 9.90 Compound 2p

438.58 13.10 Compound 2q

473.51 14.30 Compound 2s

460.41 18 Compound 2t

461.49 227 Comparator Compound 1

446.18 0.10 Comparator Compound 2

447.18 3.80

Certain compounds of this invention show agonistic activity of PPARδ andselectivity for PPARδ. In addition, certain compounds of this inventionshow improved clearance compared to comparator compounds. Also, certaincompounds of this invention show low hERG inhibition compared tocomparator compounds.

Example 1b Pharmacokinetic (PK) Screening (I.V.)

In this example, the intravenous PK profile of several PPARδ agonistsdisclosed herein in male CD1 mice was determined. Similar methods can beused to analyze other compounds provided herein. All compounds wereadministered separately to CD1 mice at 1 mg/kg (i.v.), except thecomparator compound to 2c was administered at 3 mg/kg (i.v.), as notedbelow.

I.V. I.V. (1 mg/kg (1 mg/kg dose) dose) High CL High CL or (mL/ or (mL/Ex. Low min/ Low min/ No. Structure CL kg) Comparator Structure CL kg)2a

Low 33

High 185 2b

Low 22 — — — 2c

Low 73

High 270* 2d

Low 25

Due to low expo- sure data could not be meas- ured 2e

Low 70

High 185 2f

— — — — — 2g

— — — — — 2h

Low 25 — — — 2i

— — — — — 2j

Low 38 — — — 2k

Low 17 — — — 2l

— — — — — 2m

Low 85 — — — 2n

Low 62

Due to low expo- sure data could not be meas- ured 2o

— — — — — 2p

— — — — — 2q

Low 11 — — — *3 mg/kg i.v. dose

High or low clearance (CL) values were assigned based on the reportedvalue for hepatic blood flow in mice (CL=85 mL/min/kg). Plasma CL valueswere obtained from i.v. pharmacokinetic profiles of the compounds inCD-1 mice after administration of either 1 mg/kg or 3 mg/kg doses. SeeBoxenbaum H. (1980) Interspecies variation in liver weight, hepaticblood flow and antipyrine intrinsic clearance in extrapolation ofBenzodiazepines and phenytoin. J. Pharmacokinet Biopharm 8: 165-176,incorporated herein by reference.

The compounds of the invention have desirable clearance profiles,improved exposure and/or improved half-life characteristics over theirrespective comparator compounds.

Example 2 Synthetic Preparation of Compound Embodiments Abbreviations

-   -   Me methyl    -   Et ethyl    -   nPr n-propyl    -   iPr isopropyl    -   cPr cyclopropyl    -   nBu n-butyl    -   iBu isobutyl    -   tBu tert-butyl    -   Boc tert-butyloxycarbonyl    -   Ac acetyl    -   Ph phenyl    -   Tf trifluoromethanesulfonyl    -   Ts 4-methylphenylsulfonyl    -   DIAD diisopropyl azodicarboxylate    -   EDCI 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide    -   HOBt 1-hydroxybenzotriazole    -   HATU        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate    -   HBTU N,N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium        hexafluorophosphate    -   NBS N-bromosuccinimide    -   DIPEA diisopropylethylamine    -   mCPBA m-chloroperoxybenzoic acid    -   Togni's reagent        3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole    -   DCM dichloromethane    -   DME dimethoxyethane    -   DMF N,N-dimethylformamide    -   DMF.DMA N,N-dimethylformamide dimethyl acetal    -   DMSO dimethylsulfoxide    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   MW microwave irradiation    -   aq Aqueous    -   M concentration expressed in mol/L    -   RT room temperature    -   TLC thin layer chromatography    -   HPLC high-performance liquid chromatography    -   MPLC medium pressure liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   ESI+ Electrospray ionization positive mode    -   ESI− Electrospray ionization negative mode    -   ¹H NMR (DMSO-d₆) δ (ppm) of peak in ¹H NMR in DMSO-d₆    -   s singlet (spectrum)    -   d doublet (spectrum)    -   t triplet (spectrum)    -   q quartet (spectrum)    -   dd double doublet (spectrum)    -   br broad line (spectrum)    -   m multiplet (spectrum)

Example-2a Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2a)

Step-1: Synthesis of (R)-3,7-dimethyloct-6-enoic acid

In a 5 L three neck round bottom flask, (R)-pulegone (150.0 g, 986.84mmol) was purged with HCl gas for 3 h at −30° C. The reaction mixturewas transferred to re-sealable reaction tube and mixture allowed tostand at RT for 12 h. The mixture was treated with NaOH solution (4N, 3L) and resulting mixture was stirred at RT for further 12 h. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water (1000 mL) and washed with diethyl ether (3×1000 mL).The aqueous layer was acidified (pH 4) with dilute HCl before extractingwith diethyl ether (3×1000 mL). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to get thetitle compound (125 g, 74.8%).

¹H NMR (300 MHz, DMSO-d₆): δ 12.01 (s, 1H), 5.07 (t, J=6.9 Hz, 1H), 2.22(dd, J=15.0, 6.0 Hz, 1H), 2.03-1.78 (m, 4H), 1.64 (s, 3H), 1.56 (s, 3H),1.36-1.17 (m, 2H), 0.88 (d, J=6.6 Hz, 3H).

Step-2: Synthesis of ethyl (R)-3,7-dimethyloct-6-enoate

In a 5 L round bottom flask, a suspension of (R)-3,7-dimethyloct-6-enoicacid (100.0 g, 587.41 mmol) and K₂CO₃ (243.59 g, 1762.23 mmol) in DMF(1000 mL) was treated with ethyl bromide (95.94 g, 881.12 mmol) at RT.The reaction mixture was stirred at RT for 2 h. Upon completion ofreaction (monitored by TLC), the reaction mixture was diluted with water(1000 mL) and extracted with diethyl ether (3×1000 mL). The combinedorganic extracts were dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to get the title compound (101.1 g (86.7%).

¹H NMR (300 MHz, CDCl₃): δ 5.08 (t, J=6.9 Hz, 1H), 4.12 (q, J=7.2 Hz,2H), 2.29 (dd, J=14.7, 6.0 Hz, 1H), 2.12-2.05 (m, 1H), 1.99-1.94 (m,3H), 1.66 (s, 3H), 1.58 (s, 3H), 1.39-1.16 (m, 2H), 1.24 (t, J=6.9 Hz,3H), 0.93 (d, J=6.6 Hz, 3H).

Step-3: Synthesis of ethyl(3R)-5-(3,3-dimethyloxiran-2-yl)-3-methylpentanoate

In a 5 L round bottom flask, to a solution of ethyl(R)-3,7-dimethyloct-6-enoate (100.0 g, 504.51 mmol) in diethyl ether (1L) was added a solution of 65% mCPBA (267.51 g, 1.01 mol) in diethylether (1 L) dropwise at −30° C. Once the addition was complete, themixture was warmed to 0° C. and stirred at same temperature for 6 h,before allowing it to stand overnight (˜14 h) at 0-3° C. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasdiluted with diethyl ether (1 L) and washed with 1N NaOH (2×1 L),followed by water (1 L). The organic layer was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordthe title compound (99.5 g, 92.0%).

¹H NMR (300 MHz, CDCl₃): δ 4.12 (q, J=7.2 Hz, 2H), 2.69 (t, J=5.4 Hz,1H), 2.30 (dd, J=8.7, 1.5 Hz 1H), 2.17-2.09 (m, 1H), 2.04-1.97 (m, 1H),1.55-1.42 (m, 4H), 1.30 (s, 3H), 1.27 (s, 3H), 1.25 (t, J=7.2 Hz, 3H),0.95 (d, J=6.6 Hz, 3H).

Step-4: Synthesis of ethyl (R)-3-methyl-6-oxohexanoate

In a 5 L round bottom flask, a solution of ethyl(3R)-5-(3,3-dimethyloxiran-2-yl)-3-methylpentanoate (99.0 g, 462.07mmol) in 1,4-dioxane (1 L) was treated with a solution of NaIO₄ (296.49g, 1.386 mol) in water (1 L) at RT. The reaction mixture was stirred atsame temperature for 12 h. Upon completion of reaction (monitored byTLC), the inorganic salts were filtered through Celite® pad and filtratewas extracted with EtOAc (3×1 L). The combined organic extract waswashed with water, brine and dried over anhydrous Na₂SO₄. The solutionwas concentrated under reduced pressure to afford the title compound(79.56 g, 99.3%).

¹H NMR (300 MHz, CDCl₃): δ 9.79 (s, 1H), 4.11 (q, J=7.2 Hz, 2H),2.48-2.43 (m, 2H), 2.27 (dd, J=15, 6.6 Hz, 1H), 2.17-2.10 (m, 1H),2.02-1.96 (m, 1H), 1.72-1.66 (m, 1H), 1.54-1.50 (m, 1H), 1.25 (t, J=7.2Hz, 3H), 0.96 (d, J=6.6 Hz, 3H).

Step 5: Synthesis of ethyl (R)-6-hydroxy-3-methylhexanoate

In a 1 L round bottom flask, a solution of ethyl(R)-3-methyl-6-oxohexanoate (79.0 g, 458.76 mmol) in methanol (400 mL)was treated with NaBH₄ (27.75 g, 734.02 mmol) at RT. The reactionmixture was stirred at RT for 2 h. Upon completion of reaction(monitored by TLC), the reaction mixture was diluted with water (500 mL)and extracted with EtOAc (3×500 mL). The combined organic extract wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure toget the title compound (70.0 g).

¹H NMR (300 MHz, CDCl₃): δ 4.12 (q, J=7.2 Hz, 2H), 3.64 (t, J=6.3 Hz,2H), 2.30 (dd, J=14.7, 6.6 Hz, 1H), 2.17-2.09 (m, 1H), 2.02-1.96 (m,1H), 1.67-1.56 (m, 5H), 1.26 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

Step-6: Synthesis of ethyl (R)-6-bromo-3-methylhexanoate

In a 1 L round bottom flask, a solution of ethyl(R)-6-hydroxy-3-methylhexanoate (65.0 g, 373.56 mmol) in DCM (650 mL)was treated with PBr₃ (101.0 g, 373.56 mmol) at RT. The reaction mixturewas stirred at RT for 3 h. Upon completion of reaction (monitored byTLC), the reaction mixture was diluted with water (500 mL) and extractedwith diethyl ether (3×500 mL). The organic extract was separated anddried over anhydrous Na₂SO₄. The solvent was removed under reducedpressure. The desired product was obtained (57.12 g) was used directlyin the next step without further purifications.

Step-7: Synthesis of N-(prop-2-yn-1-yl)-4-(trifluoromethoxy)benzamide

In a 500 mL round bottom flask, a stirred solution of4-(trifluoromethoxy)benzoic acid (20.0 g, 97.08 mmol) andprop-2-yn-1-amine (6.44 g, 116.49 mmol) in DMF (200 mL) was treatedsequentially with EDCI·HCl (22.24 g, 116.49 mmol), HOBt (16.01 g, 116.49mmol) and Et₃N (20.4 mL, 145.62 mmol) at RT under nitrogen atmosphere.The reaction mixture was stirred at RT for 12 h under nitrogenatmosphere. Upon completion of reaction (monitored by TLC), the reactionmixture was diluted with ice cold water and solid precipitated out. Thesolid was filtered and dried under reduced pressure to yield the titlecompound (22.0 g, 95.4%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.08 (brs, 1H), 7.99 (d, J=8.7 Hz, 2H),7.48 (d, J=8.1 Hz, 2H), 4.05-4.03 (m, 2H), 3.14 (t, J=2.4 Hz, 1H).

LCMS (ESI₊, m/z): 244.2 (M+H)⁺.

Step-8: Synthesis of1-(2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazole

In a 500 mL resealable tube, a solution ofN-(prop-2-yn-1-yl)-4-(trifluoromethoxy)benzamide (15.0 g, 61.73 mmol)and 2-methoxybenzyl amine (21.10 g, 154.32 mmol) in toluene (150 mL) wastreated with Zn(OTf)₂ (2.30 g, 6.17 mmol) at RT under nitrogenatmosphere. The reaction mixture was heated at 120° C. for 12 h. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water and extracted with EtOAc (3×100 mL). The organicextract was washed with saturated NaHCO₃, brine and dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure and residueobtained was purified by silica gel column chromatography (elution, 25%EtOAc in hexanes) to yield the title compound (15.2 g, 67.8%).

¹H NMR (300 MHz, DMSO-d₆): δ 7.55 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz,2H), 7.28 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.91-6.86 (m, 2H), 6.37 (d,J=7.5 Hz, 1H), 5.14 (s, 2H), 3.80 (s, 3H), 2.08 (s, 3H).

¹⁹F NMR (300 MHz, DMSO-d₆): δ−52.03.

LCMS (ESI+, m/z): 363.6 (M+H)⁺.

Step-9: Synthesis of2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenol

In a 500 mL round bottom flask, a solution of1-(2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazole(30.0 g, 82.64 mmol) in dichloromethane (300 mL) was treated with BBr₃(30.0 mL, 82.64 mmol) drop wise at 0° C. The reaction mixture wasstirred at RT for 2 h. Upon completion of reaction (monitored by TLC),the reaction mixture was basified (pH ˜9) with aqueous NaHCO₃ andextracted with EtOAc. The organic extract was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound (27.1 g, 94.4%).

¹H NMR (300 MHz, DMSO-d₆): δ 9.93 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.39(d, J=8.1 Hz, 2H), 7.11-7.06 (m, 1H), 6.91-6.82 (m, 2H), 6.70 (t, J=6.9Hz, 1H), 6.27 (d, J=7.8 Hz, 1H), 5.09 (s, 2H), 2.06 (s, 3H).

¹⁹F NMR (300 MHz, DMSO-d₆): δ −56.76.

LCMS (ESI+, m/z): 349.3 (M+H)⁺.

Step-10: Synthesis of ethyl(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

In a 250 mL round bottom flask, a stirred solution of2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenol(10.0 g, 28.71 mmol) in DMF (100 mL) was treated with KOtBu (9.66 g,86.13 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (20.33 g, 86.13mmol) at RT under nitrogen atmosphere. The resulting reaction mixturewas stirred at RT for 2 h. Upon completion of the reaction (monitored byTLC), the reaction mixture quenched with ice cold water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄· and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (gradientelution, 15-30% EtOAc in hexanes) to afford the title compound (7.5 g,52.1%).

LCMS (ESI+, m/z): 505.4 (M+H)⁺.

Step-11: Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2a)

In a 250 mL round bottom flask, a stirred solution of ethyl(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(7.5 g, 14.86 mmol) in THF (75 mL), ethanol (32 mL) and water (32 mL)was treated with lithium hydroxide monohydrate (3.12 g, 74.33 mmol) atRT. The reaction mixture was stirred at RT for 12 h. Upon completion ofreaction (monitored by TLC), the reaction mixture was concentrated underreduced pressure. The residue obtained was washed with EtOAc, dilutedwith cold water and acidified (pH ˜5) with 1N HCl. The solid wasfiltered and dried under reduced pressure to give the title compound(5.3 g, 75.7%).

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 11.70 (brs, 1H), 7.57 (d, J=8.4 Hz,2H), 7.32 (d, J=8.4 Hz, 2H), 7.24 (t, J=7.2 Hz, 1H), 7.01 (d, J=8.4 Hz,1H), 6.89 (s, 1H), 6.85 (t, J=7.2 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 5.16(s, 2H), 4.02 (t, J=6.4 Hz, 2H), 2.20 (dd, J=14.8, 6.0 Hz, 1H), 2.11 (s,3H), 2.06-2.00 (m, 1H), 1.90-1.88 (m, 1H), 1.75-1.71 (m, 2H), 1.48-1.45(m, 1H), 1.33-1.29 (m, 1H), 0.91 (d, J=6.8 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −56.80

LCMS (ESI+, m/z): 477.8 (M+H)⁺.

HPLC: 98.19% (210 nm).

Example-2b Synthesis of(R)-6-(2-((2-(4-chlorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2b)

Scheme:

Step-1: Synthesis of 4-chloro-N-(prop-2-yn-1-yl)benzamide

The title compound was synthesized from 4-chlorobenzoic acid (5.0 g,31.94 mmol) and prop-2-yn-1-amine (1.75 g, 31.94 mmol) following theexperimental procedure described in step-7 of Example-2a.

Yield: 4.52 g (73.0%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (brs, 1H), 7.85 (d, J=8.8 Hz, 2H),7.53 (d, J=8.8 Hz, 2H), 4.04-4.02 (m, 2H), 3.12 (t, J=2.8 Hz, 1H).

LCMS (ESI+, m/z): 194.0, 196.0 (M+H)⁺.

Step-2: Synthesis of2-(4-chlorophenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole

The title compound was synthesized from4-chloro-N-(prop-2-yn-1-yl)benzamide (1.0 g, 5.16 mmol) and2-methoxybenzyl amine (1.06 g, 7.74 mmol) following the experimentalprocedure described in step-8 of Example-2a.

Yield: 0.81 g (51.1%).

¹H NMR (400 MHz, CDCl₃): δ 7.41 (d, J=8.8 Hz, 2H), 7.30-725 (m, 3H),6.98 (s, 1H), 6.93-6.88 (m, 2H), 6.58 (d, J=7.2 Hz, 1H), 5.09 (s, 2H),3.86 (s, 3H), 2.11 (s, 3H),

LCMS (ESI+, m/z): 313.1, 315.1 (M+H)⁺.

Step-3: Synthesis of2-((2-(4-chlorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from2-(4-chlorophenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole (0.8 g,2.56 mmol) following the experimental procedure described in step-9 ofExample-2a.

Yield: 0.62 g (81.15%).

LCMS (ESI+, m/z): 299.3, 301.3 (M+H)⁺.

Step-4: Synthesis of ethyl(R)-6-(2-((2-(4-chlorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate

The title compound was synthesized from2-((2-(4-chlorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol (0.6 g,2.01 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.186 g, 1.48 mmol)following the experimental procedure described in step-10 of Example-2a.

Yield: 0.321 g (35.1%).

LCMS (ESI+, m/z): 454.5, 456.5 (M+H)⁺.

Step-5: Synthesis(R)-6-(2-((2-(4-chlorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoic acid (Compound 2b)

The title compound was synthesized from ethyl(R)-6-(2-((2-(4-chlorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate(0.3 g, 0.66 mmol) following the experimental procedure described instep-11 of Example-2a and purified by preparative silica gel thin layerchromatography (elution, 4% MeOH—CH₂Cl₂).

Yield: 0.05 g (18%).

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 7.48 (d, J=8.4 Hz, 2H), 7.40 (d,J=8.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.88 (s,1H), 6.84 (t, J=7.6 Hz, 1H), 6.51 (d, J=7.2 Hz, 1H), 5.14 (s, 2H), 3.99(t, J=5.6 Hz, 2H), 2.19-2.16 (m, 1H), 2.09 (s, 3H), 2.06-2.00 (m, 1H),1.93-1.86 (m, 1H), 1.72-1.67 (m, 2H), 1.45-1.42 (m, 1H), 1.32-1.26 (m,1H), 0.91 (d, J=6.4 Hz, 3H).

LCMS (ESI+, m/z): 427.2, 429.2 (M+H)⁺.

HPLC: 95.84% (210 nm).

Example-2c Synthesis of(R)-6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoic acid (Compound 2c)

Scheme:

Step-1: Synthesis of ethyl(R)-6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate

In a 50 mL round bottom flask, a stirred solution of2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol(0.2 g, 0.60 mmol) (a procedure for the preparation of which isdisclosed in U.S. Application No. 62/061,483, incorporated herein byreference) in DMF (5 mL) was treated with K₂CO₃ (0.25 g, 1.81 mmol) andethyl (R)-6-bromo-3-methylhexanoate (0.42 g, 1.81 mmol) at RT undernitrogen atmosphere. The resulting reaction mixture was heated 60° C.for 12 h. Upon completion of the reaction (monitored by TLC), thereaction mixture was quenched with ice cold water and extracted withethyl acetate (25 mL×3). The combined organic extract was washed withbrine, dried over anhydrous Na₂SO₄· and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (gradient elution, 15-30% EtOAc in hexanes) to afford thetitle compound (0.181 g, 61.2%).

LCMS (ESI+, m/z): 487.3 (M+H)⁺.

Step-2: Synthesis of(R)-6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoic acid (Compound 2c)

The title compound was synthesized from ethyl(R)-6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate(0.180 g, 0.37 mmol) following the experimental procedure described instep-11 of Example-2a and purified by preparative HPLC [Luna (250mm×21.20 mm, 50; flow: 18.0 ml/min; mobile phase: AB=0.1% TFA inwater/MeCN; T/% B=0/20, 2/20/8/70].

Yield: 0.04 g (23.6%).

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 7.68 (d, J=8.8 Hz, 2H), 7.65 (s,1H), 7.50 (d, J=8.8 Hz, 2H), 7.24 (t, J=8.0 Hz 1H), 7.02 (d, J=8.0 Hz,1H), 6.90-6.84 (m, 3H), 6.57-6.56 (m, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.18(s, 2H), 4.02 (d, J=6.0 Hz, 2H), 2.19-2.15 (m, 1H), 2.10 (s, 3H),2.04-1.98 (m, 1H), 1.91-1.86 (m, 1H), 1.72-1.70 (m, 2H), 1.47-1.42 (m,1H), 1.31-1.29 (m, 1H), 0.89 (d, J=6.8 Hz, 3H).

LCMS (ESI+, m/z): 459.2 (M+H)⁺.

HPLC: 97.50% (210 nm).

Example-2d Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2d)

Scheme:

Step-1: Synthesis of N-(prop-2-yn-1-yl)-4-(trifluoromethyl)benzamide

In a 500 mL round bottom flask, a stirred solution of4-(trifluoromethyl)benzoic acid (10 g, 52.63 mmol) and prop-2-yn-1-amine(3.47 g, 63.15 mmol) in DMF (200 mL) was treated sequentially withEDCI·HCl (20.09 g, 105.2 mmol), HOBt (14.2 g, 105.2 mmol) and Et₃N (14.6mL, 105.2 mmol) at RT under nitrogen atmosphere. The reaction mixturewas stirred at RT for 12 h under nitrogen atmosphere. Upon completion ofreaction (monitored by TLC), the reaction mixture was diluted with icecold water and solid precipitated out. The solid was filtered and driedunder reduced pressure to yield the title compound (8.42 g, 70.5%).

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, J=8.1 Hz, 2H), 7.71 (d, J=8.8 Hz,2H), 6.47 (brs, 1H), 4.28-4.62 (m, 2H), 3.12 (t, J=2.4 Hz, 1H).

LCMS (ESI+, m/z): 228.2 (M+H)⁺.

Step-2: Synthesis of1-(2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole

In a 500 mL resealable reaction tube, a solution ofN-(prop-2-yn-1-yl)-4-(trifluoromethyl)benzamide (13.3 g, 58.59 mmol) and2-methoxybenzyl amine (12.0 g, 87.84 mmol) in toluene (150 mL) wastreated with Zn(OTf)₂ (6.67 g, 17.5 mmol) at RT under nitrogenatmosphere. The reaction mixture was heated at 110° C. for 12 h. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water and extracted with EtOAc (3×100 mL). The combinedorganic extract was washed with saturated NaHCO₃, brine and dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressureand the residue obtained was purified by silica gel columnchromatography (elution, 25% EtOAc in hexanes) to afford the titlecompound (17.3 g, 85.3%).

¹H NMR (400 MHz, CDCl₃): δ 7.59-7.54 (m, 4H), 7.30-7.23 (m, 1H), 7.00(s, 1H), 6.91-6.86 (m, 2H), 6.57 (d, J=7.2 Hz, 1H), 5.11 (s, 2H), 3.84(s, 3H), 2.11 (s, 3H).

LCMS (ESI+, m/z): 347.3 (M+H)⁺.

Step-3: Synthesis of2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol

In a 500 mL round bottom flask, a solution of1-(2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole(17.3 g, 49.94 mmol) in DCM (150 mL) was treated with BBr₃ (1.0 M, 90.0mL) drop wise at 0° C. The reaction mixture was stirred at RT for 4 h.Upon completion of reaction (monitored by TLC), the reaction mixture wasbasified (pH ˜9) with aqueous NaHCO₃ and extracted with EtOAc (3×500mL). The combined organic extract was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (19.2g, crude).

¹H NMR (400 MHz, DMSO-d₆): δ 9.99 (s, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.77(d, J=8.4 Hz, 2H), 7.33 (s, 1H), 7.14-7.10 (m, 1H), 6.83 (d, J=8.0 Hz,1H), 6.74-6.70 (m, 1H), 6.55 (d, J=6.8 Hz, 1H), 5.21 (s, 2H), 2.16 (s,3H).

LCMS (ESI+, m/z): 333.3 (M+H)⁺.

Step-4: Synthesis of ethyl(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

In a 250 mL round bottom flask, a stirred solution of2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol (4.0 g, 12.0 mmol) in DMF (100mL) was treated with KOtBu (4.03 g, 36.1 mmol) and ethyl(R)-6-bromo-3-methylhexanoate (8.52 g, 36.10 mmol) at RT under nitrogenatmosphere. The resulting reaction mixture was stirred at RT for 12 h.Upon completion of the reaction (monitored by TLC), the reaction mixturequenched with ice cold water and extracted with EtOAc (3×100 mL). Thecombined organic extract was washed with brine, dried over anhydrousNa₂SO₄· and concentrated under reduced pressure. The residue obtainedwas purified by silica gel column chromatography (gradient elution,15-30% EtOAc in hexanes) to afford the title compound (3.31 g, 56.3%).

LCMS (ESI+, m/z): 489.3 (M+H)⁺.

Step-5: Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2d)

In a 250 mL round bottom flask, a stirred solution of ethyl(R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(3.3 g, 6.75 mmol) in THF (30 mL), ethanol (10 mL) and water (10 mL) wastreated with lithium hydroxide monohydrate (1.42 g, 33.8 mmol) at RT.The reaction mixture was stirred at RT for 12 h. Upon completion ofreaction (monitored by TLC), the reaction mixture was concentrated underreduced pressure. The residue obtained was washed with EtOAc, dilutedwith cold water and acidified (pH ˜5) with 1N HCl. The solid obtainedwas filtered and dried under reduced pressure to give the title compound(1.12 g, 36.0%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (brs, 1H), 7.71 (d, J=8.4 Hz, 2H),7.62 (d, J=8.4 Hz, 2H), 7.26-7.21 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93(s, 1H), 6.86-6.83 (m, 1H), 6.38 (d, J=6.8 Hz, 1H), 5.16 (s, 2H), 3.98(t, J=6.0 Hz, 2H), 2.19-2.14 (m, 1H), 2.08 (s, 3H), 1.99-1.93 (m, 1H),1.84-1.76 (m, 1H), 1.67-1.65 (m, 2H), 1.45-1.42 (m, 1H), 1.28-1.18 (m,1H), 0.83 (d, J=6.4 Hz, 3H)¹⁹F NMR (400 MHz, DMSO-d₆): δ −56.4

LCMS (ESI+, m/z): 460.8 (M+H)⁺.

HPLC: 98.89% (210 nm).

Preparation of Polymorphs and Salts of Compound 2d

Various forms of compound 2d can be formed from differentcrystallization experiments, as detailed below.

Compound 2d Form B

New Form B of Compound 2d was obtained by slurrying Compound 2d in ethylacetate at 50° C., 2-propanol at 50° C., acetone at 25° C., water at 25°C., water/methanol at 25° C., or ethanol at 25° C.

Compound 2d Form C

New Form C of Compound 2d was obtained by slurrying Compound 2d inacetonitrile at 50° C., water/acetonitrile at 4° C., and2-methyltetrahydrofuran at 4° C.

Compound 2d Form D

New Form D of Compound 2d was obtained by slurrying Compound 2d incyclopentyl methyl ether at 50° C., toluene at 25° C., and fromevaporative crystallization from dichloromethane.

Compound 2d Form E

New Form E Compound 2d was obtained by slurrying Compound 2d in methanolat 25° C.

Preparation of Hemisulfate Salt Form 1 of Compound 2d

In a 50 mL vial was dissolved 883.2 mg of Compound 2d was dissolved in35 mL methanol. Then, H₂SO₄ (1920 μL, 1M in H₂O, 1 equivalent) waspipetted in. The solvent was allowed to evaporate under N₂. Onceevaporated, 2-propanol (18 mL) was pipetted in followed by a stir bar.The vial was capped and placed on a 50° C. stir plate for 1 hour, thenthe temperature was dropped to 25° C., where it stirred for 1 day. After1 day, the solids were filtered under vacuum and allowed to air dry.

¹H NMR (400 MHz, DMSO-d₆): δ 7.85 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz,2H), 7.36 (s, 1H), 7.27 (t, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.85(t, J=7.6 Hz, 1H), 6.62 (d, J=7.2 Hz, 1H), 5.26 (s, 2H), 3.96 (t, J=6.0Hz, 2H), 2.21-2.16 (m, 4H), 1.96 (dd, J=8.0, 15.2 Hz, 1H), 1.83-1.80 (m,1H), 1.67-1.59 (m, 2H), 1.35-1.31 (m, 1H), 1.28-1.18 (m, 1H), 0.85 (d,J=6.4 Hz, 3H).

Mass Spectrum (ESI) m/e 461.2.

Elemental Analysis: Calculated: C, 58.93%; H, 5.54%; N, 5.50%; S, 3.15.Observed: C, 58.30%; H, 5.36%; N, 5.42%; S, 3.47.

The hemisulfate salt form 1 of Compound 2d was also obtained accordingto the same manner as that mentioned above using acetonitrile (18 mL) asa solvent instead of 2-propanol (18 mL).

Preparation of Hemisulfate Salt Form 2 of Compound 2d

Approximately 90 to 110 mg of hemisulfate form 1 of Compound 2d wasweighed out and transferred to a 4 mL amber glass vial followed by 0.8mL of methanol and a magnetic stir bar. The vial was sealed and placedonto a temperature controlled stir plate set to 25° C. and stirred for15 days at 500 rpm. The solid isolate from this experiment, identifiedas hemisulfate form 2 of Compound 2d, was obtained and characterized, inparticular, by XRPD.

Example-2e Synthesis of(E)-4-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hex-4-enoicacid (Compound 2e)

Scheme:

Step-1: Synthesis of methyl(E)-4-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hex-4-enoate

The title compound was synthesized from2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenol(0.3 g, 0.86 mmol) and methyl (E)-6-bromo-4-methylhex-4-enoate (0.57 g,2.58 mmol) (a procedure for the preparation of which is disclosed inU.S. Application No. 62/061,483, incorporated herein by reference)following the experimental procedure described in step-1 of Example-2c.

Yield: 0.180 g.

LCMS (ESI+, m/z): 489.4 (M+H)⁺.

Step-2: Synthesis of(E)-4-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hex-4-enoicacid (Compound 2e)

The title compound was synthesized from methyl(E)-4-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hex-4-enoate(0.18 g, 0.36 mmol) following the experimental procedure described instep-11 of Example-2a.

¹H NMR (400 MHz, DMSO-d₆): δ 7.69 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.4 Hz,2H), 7.44 (s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.83(t, J=7.2 Hz, 1H), 6.72 (d, J=6.8 Hz, 1H), 5.33-5.28 (m, 3H), 4.52 (d,J=6.4 Hz, 2H), 2.34-2.27 (m, 4H), 2.22 (s, 3H), 1.66 (s, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −56.77

LCMS (ESI+, m/z): 475.3 (M+H)⁺.

HPLC: 95.75% (210 nm).

Example-2f Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(p-tolyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 2f)

Scheme:

Step-1: Synthesis of1-(2-methoxybenzyl)-5-methyl-2-(p-tolyl)-1H-imidazole

In a 50 mL re-sealable reaction tube,2-(4-iodophenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole (0.4 g, 0.99mmol) and methyl boronic acid (0.088 g, 1.48 mmol) were dissolved indegassed toluene (10 mL) at RT under nitrogen atmosphere. Pd(OAc)₂(0.011 g, 0.049 mmol) tricyclohexyl phosphine (0.027 g, 0.09 mmol) andK₃PO₄ (0.63 g, 2.97 mmol) were added to the above solution undernitrogen atmosphere. The resulting mixture was degassed by purging argongas for 15 min, and reaction mixture was heated to 90° C. untilcompletion of the reaction (monitored by TLC). The reaction mixture wascooled to RT, diluted with cold water and washed with ethyl acetate (30mL×3). The combined organic extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to get thetitle compound (0.26 g, 89.9%).

¹H NMR (400 MHz, CDCl₃): δ 7.37 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.8 Hz,1H), 7.14 (d, J=8.4 Hz, 2H), 6.97 (s, 1H), 6.91 (d, J=8.1 Hz, 2H), 6.62(d, J=7.2 Hz, 1H), 5.12 (s, 2H), 3.84 (s, 3H), 2.34 (s, 3H), 2.10 (s,3H).

Step-2: Synthesis of2-((5-methyl-2-(p-tolyl)-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from1-(2-methoxybenzyl)-5-methyl-2-(p-tolyl)-1H-imidazole (0.25 g, 0.85mmol) following the experimental procedure described in step-9 ofExample-2a.

Yield: 0.23 g.

LCMS (ESI+, m/z): 279.3 (M+H)⁺.

Step-3: Synthesis of ethyl(R)-3-methyl-6-(2-((5-methyl-2-(p-tolyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate:

The title compound was synthesized from2-((5-methyl-2-(p-tolyl)-1H-imidazol-1-yl)methyl)phenol (0.23 g, 0.83mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.392 g, 1.65 mmol)following the experimental procedure described in step-1 of Example-2c.

Yield: 0.21 g (58.4%).

LCMS (ESI+, m/z): 436.5 (M+H)⁺.

Step-4: Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(p-tolyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 2f)

The title compound was synthesized from ethyl(R)-3-methyl-6-(2-((5-methyl-2-(p-tolyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(0.2 g, 0.46 mmol) following the experimental procedure described instep-11 of Example-2a and purified by preparative HPLC [Luna C18 (21.2mm×250 mm, 51 μm); flow: 18 mL/min; mobile phase: AB=0.1% TFA inwater/MeCN; T/% B=0/30, 2/40/8/80].

Yield: 0.029 g (15.5%).

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 7.34 (d, J=8.0 Hz, 2H), 7.25-7.22(m, 1H), 7.16 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 6.87-6.84 (m,2H), 6.48 (brs, 1H), 5.13 (s, 2H), 4.04 (t, J=6.4 Hz, 2H), 2.30 (s, 3H),2.14-2.13 (m, 1H), 2.07 (s, 3H), 2.05-1.99 (m, 1H), 1.91-1.86 (m, 1H),1.71-1.69 (m, 2H), 1.48-1.40 (m, 1H), 1.35-1.23 (m, 1H), 0.91 (d, J=8.0Hz, 3H).

LCMS (ESI+, m/z): 407.1 (M+H)⁺.

HPLC: 99.28% (210 nm).

Example-22 Synthesis of(R)-6-(2-((2-(4-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2g)

Scheme:

Step-1: Synthesis of 4-fluoro-N-(prop-2-yn-1-yl)benzamide:

The title compound was synthesized from 4-fluorobenzoic acid (5.0 g,35.68 mmol) and prop-2-yn-1-amine (2.35 g, 42.81 mmol) following theexperimental procedure described in step-7 of Example-2a.

Yield: 4.25 g (67.22%).

¹H NMR (300 MHz, CDCl₃): δ 7.82-7.77 (m, 2H), 7.12 (t, J=8.4 Hz, 2H),6.21 (bs, 1H), 4.26-4.23 (m, 2H), 2.29 (t, J=2.8 Hz, 1H).

Step-2: Synthesis of2-(4-fluorophenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole

The title compound was synthesized from4-fluoro-N-(prop-2-yn-1-yl)benzamide (3.0 g, 16.93 mmol) and2-methoxybenzyl amine (3.47 g, 25.39 mmol) following the experimentalprocedure described in step-8 of Example-2a.

Yield: 3.51 g (69.9%).

¹H NMR (300 MHz, CDCl₃): δ 7.46-7.41 (m, 2H), 7.30 (d, J=8.1 Hz, 1H),7.04-6.87 (m, 5H), 6.58 (d, J=7.2 Hz, 1H), 5.08 (s, 2H), 3.85 (s, 3H),2.11 (s, 3H).

¹⁹F NMR (300 MHz, CDCl₃): δ −113.0

LCMS (ESI+, m/z): 297.3 (M+H)⁺.

Step-3: Synthesis of2-((2-(4-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from2-(4-fluorophenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole (3.5 g,11.81 mmol) following the experimental procedure described in step-9 ofExample-2a.

Yield: 2.7 g (81.1%).

LCMS (ESI+, m/z): 283.3 (M+H)⁺.

Step-4: Synthesis of ethyl(R)-6-(2-((2-(4-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate

The title compound was synthesized from2-((2-(4-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol (0.6 g,2.12 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (1.51 g, 6.38 mmol)following the experimental procedure described in step-10 of Example-2a.

Yield: 0.62 g.

LCMS (ESI+, m/z): 439.4 (M+H)⁺.

Step-5: Synthesis of(R)-6-(2-((2-(4-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoic acid (Compound 2g)

The title compound was synthesized from ethyl(R)-6-(2-((2-(4-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate(0.62 g, 1.41 mmol) following the experimental procedure described instep-11 of Example-2a and purified by preparative HPLC [Phenomenex LunaC 18 (21.2 mm×250 mm, 5μm); flow: 15 mL/min; mobile phase: AB=0.1% TFAin water/MeCN; T/% B=0/40, 2/40/8/80].

Yield: 0.111 g (18.9%).

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 7.50-7.47 (m, 2H), 7.28-7.16 (m,3H), 7.03 (d, J=8.0 Hz, 1H), 6.89-6.85 (m, 2H), 6.46 (d, J=7.2 Hz, 1H),5.14 (s, 2H), 4.03 (t, J=5.6 Hz, 2H), 2.24-2.20 (m, 1H), 2.11 (s, 3H),2.08-2.03 (m, 1H), 1.95-1.90 (m, 1H), 1.80-1.67 (m, 2H), 1.50-1.42 (m,1H), 1.38-1.28 (m, 1H), 0.93 (d, J=6.8 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −113.00

LCMS (ESI+, m/z): 411.4 (M+H)⁺.

HPLC: 99.3% (210 nm).

Example-2 h Synthesis of6-(2-((2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-2,2-dimethylhexanoicacid (Compound 2h)

Scheme:

Step-1: Synthesis of3-fluoro-N-(prop-2-yn-1-yl)-4-(trifluoromethyl)benzamide

The title compound was synthesized from3-fluoro-4-(trifluoromethyl)benzoic acid (5.0 g, 24.03 mmol) andprop-2-yn-1-amine (1.59 g, 28.84 mmol) following the experimentalprocedure described in step-7 of Example-2a.

Yield: 4.71 g (79.7%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.25 (t, J=5.2 Hz, 1H), 7.93-7.83 (m, 3H),4.07-4.05 (m, 2H), 3.16 (t, J=2.4 Hz, 1H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ:−115.11, −60.32

LCMS (ESI+, m/z): 246.1 (M+H)⁺.

Step-2: Synthesis of2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole

The title compound was synthesized from3-fluoro-N-(prop-2-yn-1-yl)-4-(trifluoromethyl)benzamide (2.5 g, 10.1mmol) and 2-methoxybenzyl amine (2.1 g, 15.2 mmol) following theexperimental procedure described in step-8 of Example-2a.

Yield: 2.3 g (61.8%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.78 (t, J=7.8 Hz, 1H), 7.52 (d, J=12.3 Hz,1H), 7.45 (d, J=8.4 Hz, 1H), 7.30-7.24 (m, 1H), 7.04 (d, J=7.8 Hz, 1H),6.96 (s, 1H), 6.88-6.83 (m, 1H), 6.38 (d, J=7.5 Hz, 1H), 5.21 (s, 2H),3.78 (s, 3H), 2.10 (s, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ: −115.36, −59.90

LCMS (ESI+, m/z): 365.0 (M+H)⁺.

Step-3: Synthesis of2-((2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole(1.0 g, 2.74 mmol) following the experimental procedure described instep-9 of Example-2a.

Yield: 1.1 g, (crude)

LCMS (ESI+, m/z): 351.2 (M+H)⁺.

Step-4: Synthesis of ethyl6-(2-((2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-2,2-dimethylhexanoate

The title compound was synthesized from2-((2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol(0.5 g, 1.42 mmol) and ethyl 6-bromo-2,2-dimethylhexanoate (1.07 g, 4.28mmol) (procedures for the preparation of which are disclosed in U.S.Application No. 62/061,483, incorporated herein by reference) followingthe experimental procedure described in step-1 of Example-2c.

Yield: 0.31 g (41.81%).

LCMS (ESI+, m/z): 520.7 (M+H)⁺.

Step-5: Synthesis of6-(2-((2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-2,2-dimethylhexanoicacid (Compound 2h)

The title compound was synthesized from ethyl6-(2-((2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-2,2-dimethylhexanoate(0.3 g, 0.57 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.120 g, (46.4%).

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 7.73 (t, J=8.4 Hz, 1H), 7.49-7.45(m, 2H), 7.26 (m, J=7.6 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.96 (s, 1H),6.86 (t, J=7.6 Hz, 1H), 6.46 (d, J=7.2 Hz, 1H), 5.23 (s, 2H), 4.03 (t,J=6.4 Hz, 2H), 2.14 (s, 3H), 1.71-1.67 (m, 2H), 1.53-1.49 (m, 2H),1.41-1.36 (m, 2H), 1.06 (s, 6H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −115.25, −59.87

LCMS (ESI+, m/z): 493.3 (M+H)⁺.

HPLC: 97.62% (210 nm):

Example-2i Synthesis of6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)-phenoxy)-2,2-dimethylhexanoicacid (Compound 2i)

Scheme:

Step-1: Synthesis of 4-chloro-3-fluoro-N-(prop-2-yn-1-yl)benzamide

The title compound was synthesized from 4-chloro-3-fluorobenzoic acid(5.0 g, 28.73 mmol) and prop-2-yn-1-amine (1.89 g, 34.48 mmol) followingthe experimental procedure described in step-7 of Example-2a.

Yield: 5.2 g, (85.5%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.09 (t, J=5.2 Hz, 1H), 7.82 (dd, J=10.0,0.8 Hz, 1H), 7.72-7.69 (m, 2H), 4.04-4.02 (m, 2H), 3.13 (t, J=2.4 Hz,1H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ:−115.48

LCMS (ESI+, m/z): 212.0, 214.0 (M+H)⁺.

Step-2: Synthesis of2-(4-chloro-3-fluorophenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole

The title compound was synthesized from4-chloro-3-fluoro-N-(prop-2-yn-1-yl)benzamide (3.5 g, 16.54 mmol) and2-methoxybenzyl amine (4.54 g, 33.08 mmol) following the experimentalprocedure described in step-8 of Example-2a.

Yield: 1.3 g, (23.7%).

¹H NMR (300 MHz, CDCl₃): δ 7.36-7.28 (m, 3H), 7.21-7.17 (m, 1H), 6.99(brs, 1H), 6.95-6.88 (m, 2H), 6.56 (d, J=8.1 Hz, 1H), 5.11 (s, 2H), 3.87(s, 3H), 2.13 (s, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −114.79 LCMS (ESI+, m/z): 330.7, 332.7(M+H)⁺.

Step-3: Synthesis of2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-15yl)methyl)phenol

The title compound was synthesized from2-(4-chloro-3-fluorophenyl)-1-(2-methoxybenzyl)-5-methyl-1H-imidazole(1.3 g, 3.93 mmol) following the experimental procedure described instep-9 of Example-2a.

Yield: 1.1 g, (88.7%).

LCMS (ESI+, m/z): 317.0, 319.0 (M+H)⁺.

Step-4: Synthesis of ethyl6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-2,2-dimethylhexanoate

The title compound was synthesized from2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol(0.35 g, 1.11 mmol) and ethyl 6-bromo-2,2-dimethylhexanoate (0.831 g,3.32 mmol) (procedures for the preparation of which are disclosed inU.S. Application No. 62/061,483, incorporated herein by reference)following the experimental procedure described in step-10 of Example-2a.

Yield: 0.25 g, (46.3%).

LCMS (ESI+, m/z): 486.9, 488.9 (M+H)⁺.

Step-5: Synthesis of6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-2,2-dimethylhexanoicacid (Compound 2i)

The title compound was synthesized from ethyl6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-2,2-dimethylhexanoate(0.25 g, 0.51 mmol) following the experimental procedure described instep-11 of Example-2a and purified by preparative HPLC [Column: ZorbaxC18 (21.2 mm×150 mm, 5μm); Flow: 20 mL/min; mobile phase: AB=0.1% TFA inwater/MeCN; T/% B=0/20, 2/20, 8/70].

Yield: 0.070 g (29.8%)

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 12.02 (brs, 1H), 7.59 (t, J=8.0 Hz,1H), 7.38 (d, J=10.8 Hz, 1H), 7.28-7.24 (m, 2H), 7.05 (d, J=8.4 Hz, 1H),6.93 (s, 1H), 6.87 (t, J=7.6 Hz, 1H), 6.38 (d, J=7.6 Hz, 1H), 5.15 (s,2H), 4.02 (t, J=6.0 Hz, 2H), 2.10 (s, 3H), 1.69-1.65 (m, 2H), 1.50-1.46(m, 2H), 1.41-1.33 (m, 2H), 1.08 (s, 6H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −110.89

LCMS (ESI+, m/z): 459.2, 461.2 (M+H)⁺.

HPLC: 98.95% (210 nm).

Example-2i Synthesis of(R)-6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2j)

Scheme:

Step-1: Synthesis of ethyl(R)-6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate

The title compound was synthesized from2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol(0.350 g, 1.11 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.784 g,3.32 mmol) following the experimental procedure described in step-10 ofExample-2a.

Yield: 0.15 g (28.6%).

LCMS (ESI+, m/z): 472.9, 474.9 (M+H)⁺.

Step-2: Synthesis of(R)-6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2j)

The title compound was synthesized from ethyl(R)-6-(2-((2-(4-chloro-3-fluorophenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate(0.15 g, 0.32 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.115 g (81.5%).

¹H NMR (400 MHz, DMSO-d₆, 80° C.): δ 12.02 (brs, 1H), 7.61 (t, J=8.0 Hz,1H), 7.43 (d, J=10.8 Hz, 1H), 7.29-7.24 (m, 2H), 7.04 (d, J=8.4 Hz, 1H),6.99 (s, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.43 (d, J=7.6 Hz, 1H), 5.18 (s,2H), 4.00 (t, J=6.4 Hz, 2H), 2.23-2.18 (m, 1H), 2.11 (s, 3H), 2.02-1.99(m, 1H), 1.89-1.80 (m, 1H), 1.75-1.64 (m, 2H), 1.45-1.35 (m, 1H),1.31-1.25 (m, 1H), 0.87 (d, J=6.8 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −115.50

LCMS (ESI+, m/z): 445.2, 447.2 (M+H)⁺.

HPLC: 97.30% (210 nm).

Example-2k Synthesis of(R)-6-(4-fluoro-2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2k)

Scheme:

Step-1: Synthesis of1-(5-fluoro-2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole

The title compound was synthesized fromN-(prop-2-yn-1-yl)-4-(trifluoromethyl)benzamide (1.0 g, 4.39 mmol) and5-fluoro-2-methoxybenzyl amine (1.36 g, 8.79 mmol) following theexperimental procedure described in step-8 of Example-2a.

Yield: 0.901 g (56.3%).

LCMS (ESI+, m/z): 365.6 (M+H)⁺.

Step-2: Synthesis of4-fluoro-2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from1-(5-fluoro-2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole(0.45 g, 1.24 mmol) following the experimental procedure described instep-9 of Example-2a.

Yield: 0.3 g (crude).

LCMS (ESI+, m/z): 350.9 (M+H)⁺.

Step-3: Synthesis of ethyl(R)-6-(4-fluoro-2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate

The title compound was synthesized from4-fluoro-2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol(0.3 g, 0.86 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.61 g, 2.57mmol) following the experimental procedure described in step-10 ofExample-2a.

Yield: 0.2 g (46.2%).

LCMS (ESI+, m/z): 507.5 (M+H)⁺.

Step-4: Synthesis of(R)-6-(4-fluoro-2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2k)

The title compound was synthesized from ethyl(R)-6-(4-fluoro-2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate(0.1 g, 0.19 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.06 g (63.4%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (brs, 1H), 7.76 (d, J=8.0 Hz, 2H),7.67 (d, J=7.6 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.97 (s, 1H), 6.14 (brs,1H), 5.18 (s, 2H), 3.97 (brs, 2H), 2.25-2.13 (m, 1H), 2.13 (s, 3H),2.02-1.97 (m, 1H), 1.86-1.82 (m, 1H), 1.75-1.62 (m, 2H), 1.45-1.35 (m,1H), 1.29-1.19 (m, 1H), 0.86 (d, J=6.4 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −123.14, −61.17

LCMS (ESI+, m/z): 478.8 (M+H)⁺.

HPLC: 94.6% (210 nm).

Example-2l Synthesis of(R)-6-(2-((2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound V)

Scheme:

Step-1: Synthesis of 4-(difluoromethoxy)-N-(prop-2-yn-1-yl)benzamide

The title compound was synthesized from 4-(difluoromethoxy)benzoic acid(2.0 g, 10.63 mmol) and prop-2-yn-1-amine (0.70 g, 12.76 mmol) followingthe experimental procedure described in step-7 of Example-2a.

Yield: 1.61 g (66.9%).

¹H NMR (300 MHz, DMSO-d₆): δ 8.97 (t, J=5.1 Hz, 1H), 7.92 (d, J=8.7 Hz,2H), 7.36 (t, J=73.8 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 4.07-4.04 (m, 2H),3.14 (t, J=2.4 Hz, 1H).

LCMS (ESI+, m/z): 226.0 (M+H)⁺.

Step-2: Synthesis of1-(2-chlorobenzyl)-2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazole

The title compound was synthesized from4-(difluoromethoxy)-N-(prop-2-yn-1-yl)benzamide (1.6 g, 7.10 mmol) and2-chlorobenzyl amine (2.0 g, 14.21 mmol) following the experimentalprocedure described in step-8 of Example-2a.

Yield: 2.5 g (crude).

LCMS (ESI+, m/z): 349.3, 351.3 (M+H)⁺.

Step-3: Synthesis of2-(4-(difluoromethoxy)phenyl)-5-methyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole

In a 100 mL re-sealable reaction tube,1-(2-chlorobenzyl)-2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazole(1.0 g, 2.86 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.18 g,8.60 mmol) were dissolved in degassed 1,4-dioxane (10 mL) at RT undernitrogen atmosphere. Pd₂(dba)₃ (0.13 g, 0.14 mmol), Xphos (0.14 g, 0.29mmol) and KOAc (0.84 g, 8.61 mmol) were added to the above solutionunder nitrogen atmosphere. The resulting mixture was degassed by purgingargon gas for 15 min, and reaction mixture was heated to 90° C. untilcompletion of the reaction (monitored by TLC). The reaction mixture wascooled to RT. The solids were filtered through a Celite® pad andfiltrate was washed with water (2×20 mL). The organic extract was driedover anhydrous Na₂SO₄ and solution was concentrated under reducedpressure. The residue obtained was purified using Combiflash MPLC(Silasep™, gradient elutions 50-60% EtOAc in hexanes) to give the titlecompound (0.45 g, 35.7%).

LCMS (ESI+, m/z): 441.2 (M+H)⁺

Step-4: Synthesis of2-((2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol

In a 100 mL round bottom flask, a solution of2-(4-(difluoromethoxy)phenyl)-5-methyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole(0.45 g, 1.02 mmol) in THF-H₂O (1:1, 10 mL) was treated with NaBO₃·4H₂O(0.47 g, 3.07 mmol) at RT. The reaction mixture was stirred at RT for 2h. Upon completion of reaction (monitored by TLC), the reaction mixturewas diluted with water and extracted with EtOAc. The organic extract wasdried over anhydrous Na₂SO₄ and solution was concentrated under reducedpressure. The residue obtained was purified using Combiflash MPLC(Silasep™, gradient elutions, 50-60% EtOAc in hexanes) to give the titlecompound (0.33 g, 97.9%).

LCMS (ESI+, m/z): 331.4 (M+H)⁺.

Step-5: Synthesis of ethyl(R)-6-(2-((2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate

The title compound was synthesized from2-((2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol(0.33 g, 0.99 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.71 g,2.99 mmol) following the experimental procedure described in step-10 ofExample-2a.

Yield: 0.25 g (51.4%).

LCMS (ESI+, m/z): 487.6 (M+H)⁺.

Step-6: Synthesis of(R)-6-(2-((2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2l)

The title compound was synthesized from ethyl(R)-6-(2-((2-(4-(difluoromethoxy)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate(0.1 g, 0.19 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.05 g (53.2%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.50 (d, J=8.8 Hz, 2H), 7.24 (t, J=7.6 Hz,1H), 7.16 (d, J=8.8 Hz, 2H), 7.14 (d, J=74.0 Hz, 1H), 7.01 (d, J=8.8 Hz,1H), 6.87-6.83 (m, 2H), 6.46 (d, J=7.6 Hz, 1H), 5.15 (s, 2H), 4.01 (t,J=6.4 Hz, 2H), 2.23-2.18 (m, 1H), 2.09 (s, 3H), 2.08-2.02 (m, 1H),1.93-1.88 (m, 1H), 1.75-1.69 (m, 2H), 1.49-1.43 (m, 1H), 1.33-1.27 (m,1H), 0.93 (d, J=6.4 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −82.36

LCMS (ESI+, m/z): 458.9 (M+H)⁺.

HPLC: 95.49% (210 nm).

Example-2m Synthesis of(R)-3-methyl-6-(4-methyl-2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2m)

Scheme:

Step-1: Synthesis of1-(2-methoxy-5-methylbenzyl)-5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazole

The title compound was synthesized fromN-(prop-2-yn-1-yl)-4-(trifluoromethoxy)benzamide (0.7 g, 2.88 mmol) and2-methoxy-5-methylbenzyl amine (1.36 g, 8.79 mmol) following theexperimental procedure described in step-8 of Example-2a.

Yield: 0.35 g (32.3%).

¹H NMR (300 MHz, CDCl₃): δ 7.51 (d, J=6.9 Hz, 2H), 7.17 (d, J=8.0 Hz,2H), 7.09 (d, J=8.1 Hz, 1H), 6.98 (s, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.38(s, 1H), 5.08 (s, 2H), 3.83 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H).

LCMS (ESI+, m/z): 377.3 (M+H)⁺.

Step-2: Synthesis of4-methyl-2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from1-(2-methoxy-5-methylbenzyl)-5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazole(0.35 g, 0.93 mmol) following the experimental procedure described instep-9 of Example-2a.

Yield: 0.22 g (65.4%).

LCMS (ESI+, m/z): 363.3 (M+H)⁺.

Step-3: Synthesis of ethyl(R)-3-methyl-6-(4-methyl-2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

The title compound was synthesized from4-methyl-2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenol(0.1 g, 0.27 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.196 g,0.83 mmol) following the experimental procedure described in step-10 ofExample-2a.

Yield: 0.14 g (98.5%).

LCMS (ESI+, m/z): 519.0 (M+H)⁺.

Step-4: Synthesis of(R)-3-methyl-6-(4-methyl-2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2m)

The title compound was synthesized from ethyl(R)-3-methyl-6-(4-methyl-2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(0.15 g, 0.29 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.01 g (10.6%).

¹H NMR (400 MHz, DMSO-d₆, 90° C.): δ 7.57 (d, J=8.4 Hz, 2H), 7.27 (d,J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 1H), 6.85-6.82 (m, 2H), 6.36 (s, 1H),5.09 (s, 2H), 3.89 (d, J=4.8 Hz, 2H), 2.09 (s, 6H), 2.08-2.03 (m, 2H),1.86-1.82 (m, 1H), 1.60-1.59 (m, 2H), 1.38-1.18 (m, 2H), 0.87 (d, J=6.4Hz, 3H).

LCMS (ESI+, m/z): 490.8 (M+H)⁺.

HPLC: 95.7% (210 nm).

Example-2n Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2n)

Scheme:

Step-1: Synthesis of N-(prop-2-yn-1-yl)-6-(trifluoromethyl)nicotinamide

In a 100 mL round bottom flask, a stirred solution of6-(trifluoromethyl)nicotinic acid (3 g, 15.70 mmol) andprop-2-yn-1-amine (1.05 g, 18.84 mmol) in DMF (50 mL) was treated withHATU (7.2 g, 18.84 mmol) and Et₃N (3.1 mL, 23.55 mmol) at RT undernitrogen atmosphere. The resulting reaction mixture was stirred at RTfor 3 h. Upon completion of reaction (monitored by TLC), the reactionmixture was diluted with cold water and solid precipitated was filtered,washed with water and dried under reduced pressure to get the titlecompound (2.6 g, 72.6%).

¹H NMR (300 MHz, CDCl₃): δ 9.08 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.4, 2.4Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 6.62 (brs, 1H), 4.30-4.28 (m, 2H), 2.33(t, J=2.4 Hz, 1H).

LCMS (ESI+, m/z): 229.2 (M+H)⁺.

Step-2: Synthesis of5-(1-(2-methoxybenzyl)-5-methyl-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine

The title compound was synthesized fromN-(prop-2-yn-1-yl)-6-(trifluoromethyl)nicotinamide (1.0 g, 4.38 mmol)and 2-methoxyphenybenzyl amine (1.2 g, 8.77 mmol) following theexperimental procedure described in step-8 of Example-2a.

Yield: 0.8 g (52.6%).

¹H NMR (400 MHz, CDCl₃): δ 8.79 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.68(d, J=8.1 Hz, 1H), 7.31 (t, J=8.4 Hz, 1H), 7.09 (s, 1H), 6.94-6.87 (m,2H), 6.56 (d, J=7.5 Hz, 1H), 5.16 (s, 2H), 3.87 (s, 3H).

LCMS (ESI+, m/z): 348.3 (M+H)⁺.

Step-3: Synthesis of2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from5-(1-(2-methoxybenzyl)-5-methyl-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine(0.8 g, 2.31 mmol) following the experimental procedure described instep-9 of Example-2a.

Yield: 0.5 g (65.1%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.92 (s, 1H), 8.83 (s, 1H), 8.12 (d, J=8.1Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.12 (d, J=6.9 Hz, 1H), 7.02 (s, 1H),6.87 (d, J=7.8 Hz 1H), 6.73 (t, J=7.2 Hz, 1H), 6.37 (d, J=7.2 Hz, 1H),5.20 (s, 2H), 2.15 (s, 3H).

LCMS (ESI+, m/z): 334.3 (M+H)⁺.

Step-4: Synthesis of ethyl(R)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

The title compound was synthesized from2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenol(0.5 g, 1.50 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.710 g,3.00 mmol) following the experimental procedure described in step-1 ofExample-2c.

Yield: 0.45 g (61.3%).

LCMS (ESI+, m/z): 491.0 (M+H)⁺.

Step-5: Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2n)

The title compound was synthesized from ethyl(R)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(0.45 g, 0.92 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.166 g (39.2%).

¹H NMR (400 MHz, DMSO-d₆): δ11.96 (brs, 1H), 8.79 (s, 1H), 8.05 (d,J=8.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.02 (d,J=8.4 Hz, 1H), 7.00 (s, 1H), 6.84 (t, J=7.6 Hz, 1H), 6.43 (d, J=7.2 Hz,1H), 5.21 (s, 2H), 3.98 (t, J=6.0 Hz, 2H), 2.19-2.14 (m, 1H), 2.13 (s,3H), 2.03-1.94 (m, 1H), 1.85-1.80 (m, 1H), 1.68-1.66 (m, 2H), 1.38-1.36(m, 1H), 1.28-1.18 (m, 1H), 0.85 (d, J=6.4 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −66.46

LCMS (ESI+, m/z): 462.3 (M+H)⁺.

HPLC: 95.11% (210 nm).

Preparation of Meglumine Salt of Compound 2n

Two separate methods were used to generate a meglumine salt of compound2n.

Method 1

Compound 2n (102.7 mg) was combined with meglumine (43.7 mg) and 2 mL of2-propanol in a 4 mL glass vial. The vial was sealed with a cap and thecontents were subjected to sonication at 25° C. for 20 minutes followedby stirring at 50° C. for 60 minutes. The vial was then moved to a newstir plate and the slurry in the vial was stirred at 25° C.

Method 2

Compound 2n (102.2 mg) was combined with meglumine (43.2 mg) and 2 mL ofacetonitrile in a 4 mL glass vial. The vial was sealed with a cap andthe contents were subjected to sonication at 25° C. for 20 minutesfollowed by stirring at 50° C. for 60 minutes. The vial was then movedto a new stir plate and the slurry in the vial was stirred at 25° C.

For both method 1 and method 2, after 2 days of stirring at 25° C., bothsamples were centrifuged, supernatants discarded, and solids were airdried.

Preparation of Hydrate of Meglumine Salt of Compound 2n

In a 500 mL round bottom flask, a stirred solution of((R)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid (20 g, 43.33mmol) in THF (100 mL) and water (100 mL) was treated meglumine (8.45 g,43.33 mmol) at 0° C. The resulting reaction mixture was stirred at RTfor 6 h. The reaction mixture was concentrated under reduced pressureand solid obtained was dried under reduced pressure (3 h) to afford thetitle compound as a white solid (28.5 g, 98.95%).

¹H NMR (400 MHz, CD₃OD): δ 8.75 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.82(d, J=8.0 Hz 1H), 7.26 (t, J=8.4 Hz, 1H), 7.03 (s, 1H), 6.99 (d, J=8 Hz,1H), 6.85 (t, J=7.6 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.25 (s, 2H),4.09-3.99 (m, 3H), 3.97-3.77 (m, 2H), 3.74-3.61 (m, 3H), 3.29-3.06 (m,2H), 2.64 (s, 3H), 2.22 (s, 3H), 2.18-2.14 (m, 1H), 1.99-1.94 (m, 2H),1.83-1.75 (m, 2H), 1.51-1.38 (m, 1H), 1.32-1.22 (m, 1H), 0.86 (d, J=6.0Hz, 3H).

¹⁹F NMR (400 MHz, CD₃OD): δ −69.39

Elemental Analysis: Calcd for C₃₁H₄₃F₃N₄O₈. H₂O: C, 55.18; H, 6.72; N,8.30. Found: C, 54.95; H, 6.89; N, 8.07.

Moisture Content (Karl Fischer): 2.33%

Example-2o Synthesis of(R)-6-(2-((2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoic acid (Compound 2o)

Scheme:

Step-1: Synthesis of 4-(difluoromethyl)-N-(prop-2-yn-1-yl)benzamide

The title compound was synthesized from 4-(difluoromethyl)benzoic acid(2.0 g, 11.61 mmol) and prop-2-yn-1-amine (0.77 g, 13.94 mmol) followingthe experimental procedure described in step-7 of Example-2a.

Yield: 1.5 g (62.5%).

¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz,2H), 6.70 (t, J=56.0 Hz, 1H), 6.47 (brs, 1H), 4.29-4.27 (m, 2H), 2.31(t, J=2.4 Hz, 1H).

Step-2: Synthesis of1-(2-bromobenzyl)-2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazole

The title compound was synthesized from4-(difluoromethyl)-N-(prop-2-yn-1-yl)benzamide (3.0 g, 14.44 mmol) and2-bromobenzyl amine (5.4 g, 28.88 mmol) following the experimentalprocedure described in step-8 of Example-2a.

Yield: 2.3 g (43.3%).

¹H NMR (300 MHz, CDCl₃): δ 7.65 (dd, J=7.8, 1.2 Hz, 1H), 7.55-7.48 (m,4H), 7.32-7.19 (m, 2H), 7.04 (m, 1H), 6.64 (t, J=56.0 Hz, 1H), 6.63-6.62(m, 1H), 5.16 (s, 2H), 2.13 (s, 3H).

LCMS (ESI+, m/z): 376.8, 378.8 (M+H)⁺.

Step-3: Synthesis of2-(4-(difluoromethyl)phenyl)-5-methyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole

The title compound was synthesized from1-(2-bromobenzyl)-2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazole(0.5 g, 1.32 mmol) following the experimental procedure described instep-3 of Example-2l.

Yield: 0.18 g (32.2%).

¹H NMR (300 MHz, CDCl₃): δ 7.92 (dd, J=7.2, 1.5 Hz, 1H), 7.59 (d, J=8.4Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.42-7.36 (m, 1H), 7.32-7.26 (m, 1H),7.02 (bs, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.62 (t, J=56.1 Hz, 1H), 5.48 (s,2H), 2.11 (s, 3H), 1.31-1.23 (s, 12).

¹⁹F NMR (300 MHz, CDCl₃): δ −111.02

LCMS (ESI+, m/z): 424.0 (M+H)⁺.

Step-4: Synthesis of2-((2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from2-(4-(difluoromethyl)phenyl)-5-methyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole(0.18 g, 0.424 mmol) following the experimental procedure described instep-4 of Example-2l.

Yield: 0.12 g (44.4%).

LCMS (ESI+, m/z): 314.7 (M+H)⁺.

Step-5: Synthesis of ethyl(R)-6-(2-((2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate

The title compound was synthesized from2-((2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenol(0.11 g, 1.5 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.25 g, 1.05mmol) following the experimental procedure described in step-1 ofExample-2c.

Yield: 0.13 g (crude).

LCMS (ESI+, m/z): 471.1 (M+H)⁺.

Step-6: Synthesis of(R)-6-(2-((2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoicacid (Compound 2o)

The title compound was synthesized from ethyl(R)-6-(2-((2-(4-(difluoromethyl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)-3-methylhexanoate(0.30 g, 0.638 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.091 g (32.3%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 7.57 (bs, 4H), 7.26-7.23 (m,1H), 7.04-7.01 (m, 1H), 7.02 (t, J=56.0 Hz, 1H), 6.93 (s, 1H), 6.90-6.84(m, 1H), 6.39-6.37 (m, 1H), 5.16 (s, 2H), 3.99 (t, J=6.4 Hz, 2H),2.19-2.17 (m, 1H), 2.09 (s, 3H), 2.02-1.97 (m, 1H), 1.86-1.84 (m, 1H),1.70-1.62 (m, 2H), 1.45-1.42 (m, 1H), 1.28-1.18 (m, 1H), 0.87 (d, J=6.4Hz, 2H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −110.00

LCMS (ESI+, m/z): 443.0 (M+H)⁺.

HPLC: 95.65% (210 nm).

Example-2p Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(4-(methylthio)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2p)

Scheme:

Step-1: Synthesis of 4-(methylthio)-N-(prop-2-yn-1-yl)benzamide

The title compound was synthesized from 4-(methylthio)benzoic acid (12.0g, 58.53 mmol) and prop-2-yn-1-amine (5.89 g, 107.14 mmol) following theexperimental procedure described in step-7 of Example-2a.

Yield: 13.81 g (94.5%).

¹H NMR (300 MHz, CDCl₃): δ 7.70 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz,2H), 6.32 (brs, 1H), 4.26-4.24 (m, 2H), 2.51 (s, 3H), 2.29 (t, J=2.7 Hz,1H).

LCMS (ESI+, m/z): 206.3 (M+H)⁺.

Step-2: Synthesis of1-(2-bromobenzyl)-5-methyl-2-(4-(methylthio)phenyl)-1H-imidazole

The title compound was synthesized from4-(methylthio)-N-(prop-2-yn-1-yl)benzamide (3.0 g, 14.63 mmol) and2-bromobenzyl amine, (4.0 g, 21.95 mmol) following the experimentalprocedure described in step-8 of Example-2a.

Yield: 4.38 g (80.3%).

LCMS (ESI+, m/z): 372.9, 374.9 (M+H)⁺.

Step-3: Synthesis of5-methyl-2-(4-(methylthio)phenyl)-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole

The title compound was synthesized from1-(2-bromobenzyl)-5-methyl-2-(4-(methylthio)phenyl)-1H-imidazole (1.5 g,4.02 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.22 g,4.82 mmol) following the experimental procedure described in step-3 ofExample-2l.

Yield: 2.1 g

LCMS (ESI+, m/z): 421.2 (M+H)⁺

Step-4: Synthesis of2-((5-methyl-2-(4-(methylthio)phenyl)-1H-imidazol-1-yl)methyl)phenol

The title compound was synthesized from5-methyl-2-(4-(methylthio)phenyl)-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole(1.0 g, 2.38 mmol) following the experimental procedure described instep-4 of Example-2l.

Yield: 0.530 g.

LCMS (ESI+, m/z): 311.4 (M+H)⁺.

Step-5: Synthesis of ethyl(R)-3-methyl-6-(2-((5-methyl-2-(4-(methylthio)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

The title compound was synthesized from2-((5-methyl-2-(4-(methylthio)phenyl)-1H-imidazol-1-yl)methyl)phenol(0.3 g, 0.96 mmol) and ethyl (R)-6-bromo-3-methylhexanoate (0.685 g,2.90 mmol) following the experimental procedure described in step-1 ofExample-2c.

Yield: 0.43 g

LCMS (ESI+, m/z): 467.3 (M+H)⁺.

Step-6: Synthesis of(R)-3-methyl-6-(2-((5-methyl-2-(4-(methylthio)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2p)

The title compound was synthesized from ethyl(R)-3-methyl-6-(2-((5-methyl-2-(4-(methylthio)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(0.310 g, 0.66 mmol) following the experimental procedure described instep-11 of Example-2a.

Yield: 0.075 g (25.7%).

¹H NMR (400 MHz, DMSO-d₆, 90° C.): δ 7.38 (d, J=8.4 Hz, 2H), 7.26-7.22(m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.88-6.84 (m, 2H), 6.42 (d, J=7.6 Hz,1H), 5.14 (s, 2H), 4.03 (t, J=6.4 Hz, 2H), 2.47 (s, 3H), 2.24-2.18 (m,1H), 2.06 (s, 3H), 2.04-1.99 (m, 1H), 1.92-1.89 (m, 1H), 1.76-1.70 (m,2H), 1.49-1.43 (m, 1H), 1.35-1.26 (m, 1H), 0.92 (d, J=6.8 Hz, 3H).

LCMS (ESI+, m/z): 439.0 (M+H)⁺.

HPLC: 98.5% (210 nm).

Example-2o Synthesis of2,2-dimethyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2q)

Scheme:

Step-1: Synthesis of ethyl2,2-dimethyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

The title compound was synthesized from2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol(0.25 g, 0.75 mmol) and ethyl 6-bromo-2,2-dimethylhexanoate (0.6 g, 2.25mmol) following the experimental procedure described in step-1 ofexample-2c.

Yield: 0.121 g.

LCMS (ESI+, m/z): 502.7 (M+H)⁺.

Step-2: Synthesis of2,2-dimethyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid

The title compound was synthesized from ethyl2,2-dimethyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(0.12 g, 0.24 mmol) following the experimental procedure described instep-11 of Example 2a.

Yield: 0.04 g (35.0%)

¹H NMR (400 MHz, DMSO-d₆): δ 7.71-7.66 (m, 4H), 7.26-7.22 (m, 1H), 7.02(d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.45 (d, J=7.6Hz, 1H), 5.20 (s, 2H), 4.03 (t, J=6.4 Hz, 2H), 2.12 (s, 3H), 1.71-1.54(m, 2H), 1.52-1.49 (m, 2H), 1.41-1.34 (m, 2H), 1.07 (s, 6H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −61.16

LCMS (ESI+, m/z): 474.8 (M+H)⁺.

HPLC: 98.49% (210 nm).

Example 2r Synthesis of(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2r)

Step-1: Synthesis of2-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-imidazole

In a 250 mL round bottom flask, a stirred solution4-(trifluoromethyl)benzaldehyde (5.0 g, 27.17 mmol) andethane-1,2-diamine (1.80 g, 29.89 mmol) in tBuOH (80 mL) was treatedwith iodine (8.60 g, 33.96 mmol) and K₂CO₃ (11.30 g, 81.51 mmol) at RT.The reaction mixture was heated at 85° C. for 3 h under nitrogenatmosphere. Upon completion of reaction (TLC), the reaction mixture wasquenched with saturated Na₂S₂O₃ solution and extracted with ethylacetate (100 mL×3). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toget desired product as a yellow solid, which was taken to next stepwithout any purification (5.1 g, 83.1%).

¹H NMR (300 MHz, DMSO-d₆): δ 8.02 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.1 Hz,2H), 3.64 (s, 4H).

¹⁹F NMR (300 MHz, DMSO-d₆): δ −66.22

LCMS (ESI+, m/z): 215.2 (M+H)⁺.

HPLC (210 nm): 90.59%

Step-2: Synthesis of 2-(4-(trifluoromethyl)phenyl)-1H-imidazole

In a 250 mL round bottom flask, a stirred solution2-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-imidazole (5.0 g, 23.36mmol) in DMSO (80 mL) was treated with K₂CO₃ (3.55 g, 25.7 mmol) and(diacetoxyiodo)benzene (8.30 g, 25.7 mmol) at RT under nitrogenatmosphere. The reaction mixture was stirred at RT for 12 h undernitrogen atmosphere. Upon completion of reaction (TLC), the reactionmixture was diluted with ice cold water and extracted with ethyl acetate(100 mL×3). The combined organic extract was washed with brine, driedover anhydrous Na₂SO₄· and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution, 40% EtOAc in hexanes) to afford the title compound as a yellowsolid (2.70 g, 54.7%)

¹H NMR (400 MHz, DMSO-d₆): δ 12.81 (brs, 1H), 8.14 (d, J=8.8 Hz, 2H),7.81 (d, J=8.8 Hz, 2H), 7.23 (s, 2H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −60.98

LCMS (ESI+, m/z): 213.0 (M+H)⁺.

Step-3: Synthesis of1-(2-methoxybenzyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazole

In a 250 mL round bottom flask, a stirred solution2-(4-(trifluoromethyl)phenyl)-1H-imidazole (6.5 g, 30.66 mmol) in DMF(70 mL) was treated with NaH (60% dispersion, 1.41 g, 36.79 mmol) at 0°C. and stirred for 30 min at same temperature under nitrogen atmosphere.After 30 min, the mixture was treated with 2-methoxybenzyl bromide (7.40g, 36.79 mmol) and reaction mixture was stirred at RT for 4 h undernitrogen atmosphere. Upon completion of reaction (TLC), the reactionmixture was quenched with saturated NH₄Cl solution and extracted withethyl acetate (100 mL×3). The combined organic extract was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution, 20% EtOAc in hexanes) to afford the titlecompound as a colorless solid (8 g, 82.5%)

¹H NMR (300 MHz, DMSO-d₆): δ 7.80 (brs, 4H), 7.30-7.26 (m, 2H), 7.10 (s,1H), 7.01 (d, J=8.1 Hz, 1H), 6.89 (t, J=6.9 Hz, 1H) 6.75 (dd, J=7.5, 1.8Hz, 1H), 5.29 (s, 2H), 3.68 (s, 3H).

¹⁹F NMR (300 MHz, DMSO-d₆): δ −61.10

LCMS (ESI+, m/z): 333.2 (M+H)⁺.

Step-4: Synthesis of5-bromo-1-(2-methoxybenzyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazole

In a 50 mL round bottom flask, a stirred solution of1-(2-methoxybenzyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazole (1 g,3.01 mmol) in DMF (10 mL) was treated with a NBS (0.643 g, 3.61 mmol) atRT under nitrogen atmosphere. The reaction mixture was stirred at 45° C.for 3 h. The reaction mixture was quenched with ice water and extractedwith ethyl acetate (30 mL×2). The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄· and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (gradient elution, 5% EtOAc in hexanes) to afford thetitle compound as a white solid (0.4 g, 33.4%).

¹H NMR (400 MHz, CDCl₃): δ 7.59 (s, 4H), 7.33-7.29 (m, 1H), 7.27 (s,1H), 6.93-6.90 (m, 2H), 6.62 (d, J=8.0 Hz, 1H), 5.24 (s, 2H), 3.85 (s,3H).

LCMS (ESI+, m/z): 410.5 (M+H)⁺.

Step-5: Synthesis of1-(2-methoxybenzyl)-5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazole

In a 20 mL re-sealable reaction tube, a solution of ZnCl₂ (0.5 M in THF,820 mg, 12.0 mL, 6.0 mmol) in THF (5 mL) was treated with CD₃MgI (1 M indiethyl ether, 890 mg, 5.3 ml, 5.0 mmol) dropwise at RT under nitrogenatmosphere. The mixture was stirred at RT for 1 h and treated with5-bromo-1-(2-methoxybenzyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazole(100 mg, 0.2 mmol) and Ni(PPh₃)₂Cl₂ (8 mg, 0.01 mmol) at sametemperature under nitrogen atmosphere. The resulting reaction mixturewas stirred at RT for 48 h under nitrogen atmosphere. Upon completion ofreaction (monitored by TLC), the reaction mixture was quenched with icecold water and extracted with EtOAc (10 mL×2). The combined organicextract was washed with brine, dried over anhydrous Na₂SO₄· andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (gradient elution, 50% EtOAc inhexanes) to afford the title compound (20 mg) contaminated withdebrominated starting material

LCMS (ESI+, m/z): 350.1 (M+H)⁺.

Step-6: Synthesis of2-((5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol

In a 10 mL round bottom flask, a solution of1-(2-methoxybenzyl)-5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazole(20 mg) in DCM (2 mL) was treated with neat BBr₃ (0.1 mL) dropwise at−78° C. under nitrogen atmosphere. The reaction mixture was stirred atRT for 3 h. Upon completion of reaction (monitored by TLC), the reactionmixture was basified (pH ˜9) with aqueous NaHCO₃ and solid obtained wasfiltered and washed with n-hexane (3×5 mL). The solid product was driedunder reduced pressure to afford the title compound (12 mg). The crudematerial was used in next step without further purification.

LCMS (ESI+, m/z): 336.3 (M+H)⁺.

Step-7: Synthesis of ethyl(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

In a 25 mL round bottom flask, a stirred solution of2-((5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol(150 mg, 0.44 mmol) in toluene (3 mL) was treated sequentially with DIAD(135 mg, 0.67 mmol) and PPh₃ (175 mg, 0.67 mmol) at RT under nitrogenatmosphere. The resulting mixture was stirred at RT for 15 min andtreated with ethyl (R)-6-bromo-3-methylhexanoate (93 mg, 0.53 mmol)under nitrogen atmosphere. The reaction mixture was gradually warmed to65° C. and stirred at same temperature for 12 h. Upon completion of thereaction (monitored by TLC), the reaction mixture was cooled to RT andquenched with ice cold water before extracting with n-hexane (50 mL).The organic extract was washed with brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The residue obtained wasfiltered through by silica gel column (gradient elution, 5-10% EtOAc inhexanes) to afford the title compound (200 mg). The material was used innext step without further purification

LCMS (ESI+, m/z): 492.4 (M+H)⁺.

Step-8: Synthesis of(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2r)

In a 500 mL round bottom flask, a stirred solution of ethyl(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(1.0 g, 2.03 mmol) in THF (10 mL), MeOH (10 mL) and water (10 mL), wastreated with lithium hydroxide monohydrate (853 mg, 20.3 mmol) at RT.The reaction mixture was stirred at RT for 16 h. Upon completion ofreaction (monitored by TLC), the reaction mixture was diluted with waterand washed with diethyl ether. The aqueous layer was neutralized with 1NHCl and solid obtained was filtered to obtain residue (400 mg). Theresidue was purified twice using preparative HPLC [Column: WATERS XBRIDGE C18 (150 mm×21.20 mm, 5.00, flow: 15.0 mL/min, mobile phase:A=water, B=MeCN, T/% B=0/30, 3/40, 10/90] to yield the title compound(40 mg).

¹H NMR (300 MHz, DMSO-d₆): δ 12.00 (br s, 1H), 7.74 (d, J=8.4 Hz, 2H),7.65 (d, J=8.4 Hz, 2H), 7.28-7.23 (m, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.95(s, 1H), 6.89-6.84 (m, 1H), 6.40 (d, J=7.5 Hz, 1H), 5.18 (s, 2H), 4.01(t, J=6.6 Hz, 2H), 2.27-2.16 (m, 1H), 2.03-1.95 (m, 1H), 1.84-1.76 (m,1H), 1.67-1.65 (m, 2H), 1.45-1.38 (m, 1H), 1.28-1.23 (m, 1H), 0.85 (d,J=6.6 Hz, 3H).

¹⁹F NMR (300 MHz, DMSO-d₆): δ −61.11

²D NMR (600 MHz, CD₃OD): δ 2.04

LCMS (ESI+, m/z): 464.4 (M+H)⁺.

HPLC: 98.21% (210 nm).

Example 2s Synthesis of(S)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2s)

Step-1: Synthesis of (S)-3,7-dimethyloct-6-enoic acid

In a 500 mL of round bottom flask, a solution of NaOH (12.92 g, 325.0mmol) in water (100 mL) was treated with AgNO₃ (25.2 g, 149.0 mmol) inwater (100 mL) at 0° C. The reaction mixture was stirred in dark for 30min and treated (3S)-3,7-dimethyloct-6-enal (10.0 g, 65.0 mmol) at 0° C.The reaction mixture was stirred at RT for 18 h. Upon completion ofreaction (monitored by TLC), the reaction mixture was filtered through aCelite® pad and washed with hot water. The combined filtrate wasacidified (pH 2) with concentrated HCl and extracted with diethyl ether.The organic extract was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue obtained was used in the next stepwithout further purification.

Yield: 10.0 g (90.9%)

¹H NMR (400 MHz, CDCl₃): δ 8.8 (brs, 1H), 5.09 (t, J=7.2 Hz, 1H),2.39-2.34 (dd, J=15.0, 6.0 Hz, 1H), 2.17-2.12 (dd, J=15.0, 6.0 Hz, 1H),2.03-1.94 (m, 3H), 1.67 (s, 3H), 1.59 (s, 3H), 1.36-1.17 (m, 2H), 0.97(d, J=6.6 Hz, 3H).

Step-2: Synthesis of ethyl (S)-3,7-dimethyloct-6-enoate

In a 500 mL round bottom flask, a suspension of(S)-3,7-dimethyloct-6-enoic acid (10.0 g, 58.0 mmol) and K₂CO₃ (20.29 g,140.0 mmol) in DMF (100 mL) was treated with ethyl bromide (8.25 g, 76.0mmol) at RT. The reaction mixture was stirred at RT for 16 h. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water (1000 mL) and extracted with diethyl ether (100mL×2). The combined organic extract was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to get the title compound (11.3 g,96.5%).

¹H NMR (300 MHz, CDCl₃): δ 5.08 (t, J=6.9 Hz, 1H), 4.12 (q, J=7.2 Hz,2H), 2.29 (dd, J=14.7, 6.0 Hz, 1H), 2.12-2.05 (m, 1H), 1.99-1.94 (m,3H), 1.67 (s, 3H), 1.59 (s, 3H), 1.39-1.16 (m, 2H), 1.24 (t, J=6.9 Hz,3H), 0.93 (d, J=6.6 Hz, 3H).

Step-3: Synthesis of Ethyl(S)-5-(3,3-dimethyloxiran-2-yl)-3-methylpentanoate

In a 5 L round bottom flask, a solution of ethyl(S)-3,7-dimethyloct-6-enoate (25.0 g, 126.0 mmol) in diethyl ether (200mL) was treated with a solution of mCPBA (65%, 32.5 g, 189.0 mmol) indiethyl ether (300 mL) dropwise at −30° C. The resulting mixture waswarmed to 0° C. and stirred at same temperature for 6 h, before allowingit to stand overnight (˜14 h) at 0-3° C. Upon completion of reaction(monitored by TLC), the reaction mixture was diluted with diethyl ether(500 L) and washed with 1N NaOH (2×1 L), followed by water (1 L). Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (24.0g, 88.8%)

¹H NMR (400 MHz, CDCl₃): δ 4.11 (q, J=7.2 Hz, 2H), 2.69 (t, J=5.4 Hz,1H), 2.30 (dd, J=8.7, 1.5 Hz, 1H), 2.17-2.09 (m, 1H), 2.04-1.98 (m, 1H),1.55-1.42 (m, 4H), 1.30 (s, 3H), 1.27 (s, 3H), 1.25 (t, J=7.2 Hz, 3H),0.96 (d, J=6.6 Hz, 3H).

Step-4: Synthesis of ethyl (S)-3-methyl-6-oxohexanoate

In a 500 mL round bottom flask, a solution of ethyl(S)-5-(3,3-dimethyloxiran-2-yl)-3-methylpentanoate (24.0 g, 11.00 mmol)in 1,4-dioxane (240 L) was treated with a solution of NaIO₄ (71.6 g,33.0 mol) in water (240 mL) at RT. The reaction mixture was stirred atsame temperature for 16 h. Upon completion of reaction (monitored byTLC), the inorganic salts were filtered through Celite® pad and filtratewas extracted with EtOAc (3×500 mL). The combined organic extract waswashed with water, brine and dried over anhydrous Na₂SO₄. The solutionwas concentrated under reduced pressure to afford the title compound (20g).

¹H NMR (300 MHz, CDCl₃): δ 9.79 (s, 1H), 4.16-4.07 (m, 2H), 2.48-2.43(m, 2H), 2.27 (dd, J=15, 6.6 Hz, 1H), 2.17-2.10 (m, 1H), 2.02-1.96 (m,1H), 1.72-1.66 (m, 1H), 1.54-1.50 (m, 1H), 1.25 (t, J=7.2 Hz, 3H), 0.95(d, J=6.6 Hz, 3H).

Step 5: Synthesis of ethyl (S)-6-hydroxy-3-methylhexanoate

In a 1 L round bottom flask, a solution of ethyl(S)-3-methyl-6-oxohexanoate (20.0 g, 116.0 mmol) in methanol (100 mL)was treated with NaBH₄ (7.0 g, 186.0 mmol) at RT. The reaction mixturewas stirred at RT for 4 h. Upon completion of reaction (monitored byTLC), the reaction mixture was diluted with water (500 mL) and extractedwith EtOAc The combined organic extract was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to get the title compound (20.0g, 99.0%).

¹H NMR (300 MHz, CDCl₃): δ 4.15-4.07 (m, 2H), 3.65 (t, J=6.3 Hz, 2H),2.30 (dd, J=14.7, 6.6 Hz, 1H), 2.17-2.09 (m, 1H), 2.02-1.96 (m, 1H),1.67-1.56 (m, 5H), 1.26 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

Step-6: Synthesis of ethyl (S)-3-methyl-6-((methylsulfonyl)oxy)hexanoate

In a 100 mL round bottom flask, a solution of ethyl(S)-6-hydroxy-3-methylhexanoate (2.5 g, 14.3 mmol) in DCM (25 mL) wastreated Et₃N (4.35 g, 43.0 mmol) and MsCl (2.45 g, 21.5 mmol) at 0° C.The reaction mixture was stirred at RT for 3 h. Upon completion ofreaction (monitored by TLC), the reaction mixture was diluted with water(50 mL) and extracted with DCM (50 mL×3). The combined organic extractwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto get desired product (2.5 g, 69.5%).

¹H NMR (300 MHz, CDCl₃): δ 4.23-4.09 (m, 4H), 3.00 (s, 3H), 2.32-2.11(m, 2H), 2.02-1.96 (m, 1H), 1.78-1.72 (m, 2H), 1.46-1.41 (m, 2H), 1.26(t, J=7.2 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H).

Step-7: Synthesis of N-(prop-2-yn-1-yl)-4-(trifluoromethyl)benzamide

In a 2 L round bottom flask, a stirred solution of4-(trifluoromethyl)benzoic acid (100 g, 5.26 mol) and prop-2-yn-1-amine(34.73 g, 6.31 mol) in DMF (1000 mL) was treated sequentially withEDCI·HCl (200.8 g, 1.05 mol), HOBt (142 g, 1.052 mol) and Et₃N (53.12 g,1.578 mol) at RT under nitrogen atmosphere. The reaction mixture wasstirred at RT for 12 h under nitrogen atmosphere. Upon completion ofreaction (monitored by TLC), the reaction mixture was diluted with icecold water and solid precipitated out. The solid was filtered and driedunder reduced pressure to afford the title compound (111 g, 93.2%).

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, J=8.1 Hz, 2H), 7.71 (d, J=8.8 Hz,2H), 6.47 (brs, 1H), 4.28-4.62 (m, 2H), 3.12 (t, J=2.4 Hz, 1H).

LCMS (ESI+, m/z): 228.2 (M+H)⁺.

Step-8: Synthesis of1-(2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole

In a 500 mL re-sealable reaction tube, a solution ofN-(prop-2-yn-1-yl)-4-(trifluoromethyl)benzamide (30 g, 132.15 mmol) and2-methoxybenzyl amine (27.31 g, 198.23 mmol) in toluene (300 mL) wastreated with Zn(OTf)₂ (15.06 g, 39.6 mmol) at RT under nitrogenatmosphere. The reaction mixture was stirred at 100° C. for 16 h. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water and extracted with EtOAc (30 mL). The organic extractwas washed with saturated NaHCO₃, brine and dried over anhydrous Na₂SO₄.The solution was concentrated under reduced pressure and residueobtained was purified by silica gel column chromatography (elution, 25%EtOAc in hexanes) to yield the title compound (30.4 g, 66.6%).

¹H NMR (400 MHz, CDCl₃): δ 7.59-7.54 (m, 4H), 7.30-7.23 (m, 1H), 7.00(s, 1H), 6.91-6.86 (m, 2H), 6.57 (d, J=7.2 Hz, 1H), 5.11 (s, 2H), 3.84(s, 3H), 2.11 (s, 3H), LCMS (ESI+, m/z): 347.3 (M+H)⁺.

Step-9: Synthesis of2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol

In a 1000 mL round bottom flask, a solution of1-(2-methoxybenzyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole(60 g, 173.4 mmol) in dichloromethane (600 mL) was treated with BBr₃ (60mL) dropwise at −78° C. The reaction mixture was stirred at RT for 3 h.Upon completion of reaction (monitored by TLC), the reaction mixture wasbasified with aqueous NaHCO₃. The solid obtained was filtered, washedwith n-hexane (500 mL×3) and dried under reduced pressure to afford thetitle compound (53.1 g, 92.3%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.99 (s, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.77(d, J=8.4 Hz, 2H), 7.33 (s, 1H), 7.14-7.10 (m, 1H), 6.83 (d, J=8.0 Hz,1H), 6.74-6.70 (m, 1H), 6.55 (d, J=6.8 Hz, 1H), 5.21 (s, 2H), 2.16 (s,3H).

LCMS (ESI+, m/z): 333.3 (M+H)⁺.

Step-10: Synthesis of ethyl(S)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

In a 100 mL round bottom flask, a stirred solution of2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenol(1.0 g, 3.0 mmol) in DMF (15 mL) was treated with K₂CO₃ (1.24 g, 9.0mmol) and ethyl (S)-3-methyl-6-((methylsulfonyl)oxy)hexanoate (1.13 g,4.5 mmol) at RT under nitrogen atmosphere. The resulting reactionmixture was stirred at 80° C. for 16 h. Upon completion of the reaction(monitored by TLC), the reaction mixture was cooled to RT; solid wasfiltered and washed with ethyl acetate. The combined filtrate wasconcentrated under reduced pressure and residue obtained was dilutedwith cold water (50 mL), before extracting with ethyl acetate (50 mL).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (gradient elution, 15-30%EtOAc in hexanes) to afford the title compound (0.8 g, 57.1%).

¹H NMR (300 MHz, CDCl₃): δ 7.59 (d, J=1.5 Hz, 4H), 7.33 (s, 1H), 7.02(d, J=0.9 Hz, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.60 (d, J=6.8 Hz, 1H),5.12 (s, 2H), 4.15-4.01 (m, 4H), 2.19-2.14 (m, 1H), 2.10-1.95 (m, 1H),2.04 (s, 3H), 1.85-1.76 (m, 2H), 1.55-1.45 (m, 1H), 1.40-1.30 (m, 1H),1.28-1.18 (m, 4H), 0.83 (d, J=6.4 Hz, 3H).

LCMS (ESI+, m/z): 488.5 (M+H)⁺.

Step-11: Synthesis of(S)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2s)

In a 50 mL round bottom flask, a stirred solution of ethyl(S)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(0.4 g, 0.81 mmol) in THF (40 mL) and water (10 mL), was treated withlithium hydroxide monohydrate (60 mg, 2.4 mmol) at RT. The reactionmixture was stirred at RT for 12 h. Upon completion of reaction(monitored by TLC), the reaction mixture was diluted with water andwashed with diethyl ether. The aqueous layer was neutralized with 1N HCland solid obtained was filtered. The solid compound was washed with 50%diethyl ether-pentane to afford the title compound as a white solid (180mg, 48.6%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (br s, 1H), 7.74 (d, J=8.4 Hz, 2H),7.65 (d, J=8.4 Hz, 2H), 7.26 (t, J=8.4 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H),6.95 (s, 1H), 6.87 (t, J=7.6 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H), 5.18 (s,2H), 3.99 (t, J=6.0 Hz, 2H), 2.19-2.14 (m, 1H), 2.10 (s, 3H), 1.99-1.93(m, 1H), 1.84-1.76 (m, 1H), 1.67-1.65 (m, 2H), 1.45-1.38 (m, 1H),1.28-1.23 (m, 1H), 0.84 (d, J=6.4 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −61.61

LCMS (ESI+, m/z): 460.7 (M+H)⁺.

HPLC: 98.65% (210 nm).

Example 2t Synthesis of(S)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2t)

Scheme:

Step-1: Synthesis of N-(prop-2-yn-1-yl)-6-(trifluoromethyl)nicotinamide

In a 3 L round bottom flask, a stirred solution of6-(trifluoromethyl)nicotinic acid (150 g, 785.34 mmol) andprop-2-yn-1-amine (51.83 g, 942.40 mmol) in DMF (1.5 L) was treated withHATU (447 g, 1177.50 mmol) and Et₃N (120 g, 1177.5 mmol) at RT undernitrogen atmosphere. The reaction mixture was stirred at RT for 3 h.Upon completion of reaction (monitored by TLC), the reaction mixture wasdiluted with ice water and precipitate obtained was filtered, washedwith water and 50% ethyl acetate in hexane. The solid compound was driedunder reduced pressure to get the title compound (137 g, 76.5%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (t, J=5.6 Hz, 1H), 9.14 (s, 1H), 8.46(d, J=8.4 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 4.12-4.10 (m, 2H), 3.20 (t,J=0.4 Hz, 1H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −66.70.

LCMS (ESI+, m/z): 229.2 (M+H)⁺.

Step-2: Synthesis of5-(1-(2-methoxybenzyl)-5-methyl-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine

In a 500 mL re-sealable reaction tube, a solution ofN-(prop-2-yn-1-yl)-6-(trifluoromethyl)nicotinamide (50 g, 219.29 mmol)and 2-methoxybenzyl amine (39.0 g, 285.08 mmol) in toluene (300 mL) wastreated with Zn(OTf)₂ (23.8 g, 65.78 mmol) at RT under nitrogenatmosphere. The reaction mixture was stirred at 110° C. for 16 h. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water and extracted with EtOAc (30 mL). The organic extractwas washed with saturated NaHCO₃, brine and dried over anhydrous Na₂SO₄.The solution was concentrated under reduced pressure and residueobtained was purified by washed with diethyl ether to yield the titlecompound (46 g, 60.65%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.94(d, J=7.6 Hz, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 7.01(s, 1H), 6.88 (t, J=8.4 Hz, 1H), 6.42 (d, J=7.2 Hz, 1H), 5.23 (s, 2H),3.78 (s, 3H), 2.13 (s, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −66.43.

Step-3: Synthesis of2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenol:

In a 1000 mL round bottom flask, a solution of5-(1-(2-methoxybenzyl)-5-methyl-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine(80 g, 230.54 mmol) in dichloromethane (800 mL) was treated with BBr₃(80 mL) dropwise at −78° C. The reaction mixture was stirred at RT for 3h. Upon completion of reaction (monitored by TLC), the reaction mixturewas basified with aqueous NaHCO₃. The solid obtained was filtered,washed with n-hexane (500 mL×3) and dried under reduced pressure toafford the title compound (65.0 g, 84.66%).

¹H NMR (400 MHz, DMSO-d₆): δ 9.94 (s, 1H), 8.83 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 7.01 (s, 1H),6.86 (d, J=8.0 Hz 1H), 6.72 (d, J=8.8 Hz, 1H), 6.36 (d, J=7.6 Hz, 1H),5.20 (s, 2H), 2.14 (s, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −66.44.

LCMS (ESI+, m/z): 334.3 (M+H)⁺.

HPLC: 99.23% (210 nm).

Step-4: Synthesis of ethyl(S)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate

In a 100 mL round bottom flask, a stirred solution of2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenol(1.0 g, 3.0 mmol) in DMF (15 mL) was treated with K₂CO₃ (1.13 g, 4.5mmol) and ethyl (S)-3-methyl-6-((methylsulfonyl)oxy)hexanoate (1.24 g,9.0 mmol) at RT under nitrogen atmosphere. The resulting reactionmixture was stirred at 80° C. for 16 h. Upon completion of the reaction(monitored by TLC), the reaction mixture was cooled to RT; solid wasfiltered and washed with ethyl acetate. The combined filtrate wasconcentrated under reduced pressure and residue obtained was dilutedwith cold water (50 mL), before extracting with ethyl acetate (50 mL).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (gradient elution, 15-30%EtOAc in hexanes) to afford the title compound (0.7 g, crude).

LCMS (ESI+, m/z): 490.2 (M+H)⁺.

Step-5: Synthesis of(S)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid (Compound 2t)

In a 50 mL round bottom flask, a stirred solution of ethyl(S)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate(0.4 g, 0.81 mmol) in THF (40 mL) and water (10 mL), was treated withlithium hydroxide monohydrate (60 mg, 2.4 mmol) at RT. The reactionmixture was stirred at RT for 12 h. Upon completion of reaction(monitored by TLC), the reaction mixture was diluted with water andwashed with diethyl ether. The aqueous layer was neutralized with 1N HCland solid obtained was filtered. The solid compound was washed with 50%diethyl ether-pentane to afford the title compound as a white solid (200mg, 53.0%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (brs, 1H), 8.81 (s, 1H), 8.06 (d,J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.05-7.02(m, 2H), 6.86 (t, J=7.6 Hz, 1H), 6.43 (d, J=6.8 Hz, 1H), 5.22 (s, 2H),3.99 (t, J=6.4 Hz, 2H), 2.22-2.14 (m, 1H), 2.14 (s, 3H), 2.01-1.86 (m,1H), 1.86-1.81 (m, 1H), 1.72-1.66 (m, 2H), 1.43-1.37 (m, 1H), 1.28-1.22(m, 1H), 0.86 (d, J=6.8 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −66.77.

LCMS (ESI+, m/z): 463.1 (M+H)⁺.

HPLC: 97.23% (210 nm).

Example 2u Synthesis of(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 2u)

Scheme:

Step-1: Synthesis of5-(4,5-dihydro-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine

In a 500 mL round bottom flask, a stirred solution6-(trifluoromethyl)nicotinaldehyde (15.0 g, 85.71 mmol) andethane-1,2-diamine (5.14 g, 85.71 mmol) in tBuOH (150 mL) was stirredfor 45 min at RT under nitrogen atmosphere. Iodine (25.8 g, 102.85 mmol)and K₂CO₃ (35.48 g, 257.13 mmol) was added and reaction mixture washeated at 85° C. for 12 h under nitrogen atmosphere. Upon completion ofreaction (monitored by TLC), the reaction mixture was quenched withsaturated Na₂S₂O₃ solution and extracted with ethyl acetate (100 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄· and concentrated under reduced pressure to give desired productas a yellow solid, which was taken to next step without any purification(13.1 g, 71.1%).

¹H NMR (300 MHz, CDCl₃): δ 9.05 (s, 1H), 8.28 (d, J=8.1 Hz, 1H), 7.74(d, J=8.1 Hz, 1H), 4.10-3.50 (bs, 4H). (note: NH proton not observed inNMR)

¹⁹F NMR (300 MHz, CDCl₃): δ −68.07

LCMS (ESI⁺, m/z): 216.2 (M+H)⁺.

Step-2: Synthesis of 5-(1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine

In a 250 mL round bottom flask, a stirred solution5-(4,5-dihydro-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine (6.0 g,27.9 mmol) in DMSO (50 mL) was treated with K₂CO₃ (4.62 g, 33.4 mmol)and (diacetoxyiodo)benzene (10.78 g, 33.4 mmol) at RT. The reactionmixture was stirred at RT for 18 h under nitrogen atmosphere. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with ice cold water and solid obtained was filtered. The solidwas washed with water and n-hexane and dried under reduced pressure toget desired product as a yellow solid (4.0 g, 67.7%).

¹H NMR (400 MHz, CDCl₃): δ 13.0 (s, 1H), 9.30 (s, 1H), 8.51 (d, J=8.4Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.16 (s, 1H).

LCMS (ESI⁺, m/z): 214.2 (M+H)⁺.

Step-3: Synthesis of5-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-(trifluoromethyl) pyridine

In a 100 mL round bottom flask, a stirred solution5-(1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine (3 g, 14.0 mmol) in DMF(30 mL) was treated with NaH (60% dispersion in oil, 1.12 g, 28.1 mmol)at 0° C. and stirred for 30 min at same temperature under nitrogenatmosphere. 2-Methoxybenzyl bromide (3.68 g, 18.3 mmol) was added to theabove mixture under nitrogen atmosphere. The reaction mixture wasstirred for 12 h at RT under nitrogen atmosphere. Upon completion ofreaction (monitored by TLC), the reaction mixture was quenched withsaturated NH₄Cl solution and extracted with ethyl acetate (200 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄· and concentrated under reduced pressure. The residue obtainedwas washed with n-hexane to afford the title compound as a white solid(3.5 g, 76.1%)

¹H NMR (300 MHz, DMSO-d₆): δ 8.96 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.98(d, J=8.1 Hz 1H), 7.39 (s, 1H), 7.28 (t, J=8.1 Hz, 1H), 7.14 (s, 1H),6.98 (d, J=8.1 Hz, 1H), 6.88 (t, J=7.2 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H),5.32 (s, 2H), 3.67 (s, 3H)

¹⁹F NMR (300 MHz, CDCl₃): δ −66.43

LCMS (ESI⁺, m/z): 334.2 (M+H)⁺.

Step-4: Synthesis of5-(5-bromo-1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine

In a 50 mL round bottom flask, a stirred solution of5-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine (3g, 9.00 mmol) in DMF (30 mL) was treated with a NBS (1.6 g, 9.00 mmol)at RT under nitrogen atmosphere. The reaction mixture was stirred at RTfor 3 h. Upon completion of reaction (monitored by TLC), the reactionmixture was quenched with ice water and extracted with ethyl acetate (30mL×2). The combined organic extract was washed with brine, dried overanhydrous Na₂SO₄· and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (elution 5%EtOAc in hexanes) to afford the title compound as a white solid (0.9 g,24.3%) and mixture (2 g) of5-(4-bromo-1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine and5-(4,5-dibromo-1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine.

¹H NMR (400 MHz, DMSO-d₆): δ 8.87 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.98(d, J=8.4 Hz 1H), 7.39 (s, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 6.47 (d, J=6.0 Hz, 1H), 5.30 (s, 2H),3.74 (s, 3H).

¹⁹F NMR (300 MHz, CDCl₃): δ −66.55

LCMS (Est, m/z): 412.2, 414.2 (M+H)⁺.

Step-5: Synthesis of5-(1-(2-methoxybenzyl)-5-(methyl-d₃)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine

In a 100 mL re-sealable reaction tube, a solution of ZnCl₂ (0.5 M inTHF, 20.0 mL, 40.0 mmol) was treated with CD₃MgI (1 M in diethyl ether,12 mL, 12.0 mmol) dropwise at RT under nitrogen atmosphere. The mixturewas stirred at RT for 1 h and treated with5-(5-bromo-1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine(200 mg, 0.486 mmol) and Ni(PPh₃)₂Cl₂ (26 mg, 0.0486 mmol) at sametemperature under nitrogen atmosphere. The resulting reaction mixturewas stirred at RT for 48 h under nitrogen atmosphere. Upon completion ofreaction (monitored by TLC), the reaction mixture was quenched with icecold water and extracted with EtOAc (10 mL×2). The combined organicextract was washed with brine, dried over anhydrous Na₂SO₄· andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (elution 50% EtOAc in hexanes) toafford the title compound (50 mg) contaminated with debrominated sideproduct, 5-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine (as indicated by NMR (˜1:1))

LCMS (ESI⁺, m/z): 351.1 (M+H)⁺.

Step-6: Synthesis of 2-((5-(methyl-d₃)-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl) methyl)phenol

In a 100 mL round bottom flask, a solution of5-(1-(2-methoxybenzyl)-5-(methyl-d₃)-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine(200 mg, 0.571 mmol) in DCM (5 mL) was treated with neat BBr₃ (0.2 mL)dropwise at −78° C. under nitrogen atmosphere. The reaction mixture wasgradually warmed to RT and stirred at RT for 3 h. Upon completion ofreaction (monitored by TLC), the reaction mixture was basified (pH ˜9)with aqueous NaHCO₃ and solid obtained was filtered and washed withn-hexane (3×5 mL). The solid product was dried under reduced pressure toafford the title compound (180 mg), which was used in next step withoutfurther purification.

LCMS (ESI⁺, m/z): 337.1 (M+H)⁺.

Step-7: Synthesis of ethyl(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-yl) methyl)phenoxy)hexanoate

In a 50 mL round bottom flask, a stirred solution of2-((5-(methyl-d₃)-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenol(180 mg, 0.365 mmol) in DMF (5 mL) was treated with K₂CO₃ (151 mg, 1.09mmol) and ethyl (R)-3-methyl-6-((methylsulfonyl)oxy)hexanoate (138 mg,0.548 mmol) at RT under nitrogen atmosphere. The resulting reactionmixture was stirred at 80° C. for 16 h under nitrogen atmosphere. Uponcompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (3×20 mL).The combined organic extract was washed with brine and dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressure.The residue obtained was flash purified by silica gel columnchromatography (gradient elution, 15-30% EtOAc in hexanes) to afford thetitle compound (258 mg), contaminated with side product, ethyl(R)-3-methyl-6-(2-((2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate.

LCMS (ESI⁺, m/z): 493.6 (M+H)⁺.

Step-8: Synthesis of(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound2u)

In a 50 mL round bottom flask, a stirred solution of ethyl(R)-3-methyl-6-(2-((5-(methyl-d₃)-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoate (250 mg, 0.508 mmol) in THF (5 mL), EtOH (1 mL) and water (5mL), was treated with lithium hydroxide monohydrate (213 mg, 5.08 mmol)at RT. The reaction mixture was stirred at RT for 16 h. Upon completionof reaction (monitored by TLC), the reaction mixture was diluted withwater and washed with diethyl ether. The aqueous layer was neutralizedwith 1N HCl and solid obtained was filtered. The solid residue obtainedwas further purified by preparative HPLC [Kinetex C18, (21.2 mm×150 mm)5.01μ; Flow: 15.0 mL/min; mobile phase: A=: 0.1% TFA, B=MeCN, T/%B=0/25, 2/35, 8/65]. The HPLC fractions were concentrated under reducedpressure and residue obtained was diluted with water, before extractingwith ethyl acetate (2×15 mL). The organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford the title compound (30.5 mg, 12.9%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (br s, 1H), 8.81 (s, 1H), 8.07 (d,J=7.2 Hz, 1H), 7.92 (d, J=8.4 Hz 1H), 7.26 (t, J=7.2 Hz, 1H), 7.04 (d,J=7.2 Hz, 1H), 7.03 (s, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.46 (d, J=7.2 Hz,1H), 5.23 (s, 2H), 3.99 (t, J=6.0 Hz, 2H), 2.28-2.17 (m, 1H), 2.02-1.96(m, 1H), 1.84-1.76 (m, 1H), 1.70-1.65 (m, 2H), 1.45-1.38 (m, 1H),1.28-1.22 (m, 1H), 0.86 (d, J=6.8 Hz, 3H).

¹⁹F NMR (400 MHz, DMSO-d₆): δ −66.45

²D NMR (600 MHz, CH₃OH): δ 2.10 (s, 3D)

LCMS (ESI⁺, m/z): 465.2 (M+H)⁺.

HPLC: 95.27% (210 nm).

Example 3 Improving Mitochondrial Biogenesis and Function in DuchenneMuscular Dystrophy (DMD) Muscle Cells

Rationale: Mitochondrial defects are observed in model systems ofDuchenne Muscular Dystrophy including, but not limited to, fatty acidmetabolism and biogenesis. See Rybalka, E., et al., Defects inmitochondrial ATP synthesis in dystrophin-deficient mdx skeletal musclesmay be caused by complex I insufficiency. PLoS One, 2014. 9(12): p.e115763. In this example, myoblast cells from a commercially availableDuchenne Muscular Dystrophy patient were treated with Compound 2d andtested for improvements in fatty acid oxidation and mitochondrialbiogenesis.

Cell culture and treatment: DMD human skeletal muscle cells were platedinto Seahorse XF plates (Agilent Technologies) and allowed todifferentiate for 7 days. Differentiated cells were treated with vehicleor compound 2d for 24 hours prior to assay in DMEM media withoutPyruvate, Glucose, Glutamine supplemented with galactose and 500carnitine.

Fatty acid oxidation assay: Mitochondria stress test components wereloaded in Krebs-Henseleit Buffer at final concentrations 2.5 μMOligomycin A (Sigma 75351); 7 μM FCCP (Sigma C2920); 1 μM both Rotenone(Sigma R8875) and Antimycin A (Sigma A8674). Following calibration, 200μL KHB mixed with control BSA (final 0.037 mM; from) or BSA-palmitate(final 0.037 mM BSA 500 μM palmitate) was added to the appropriatewells. Next the cell culture plate was placed into the Seahorse XFe96Analyzer (Agilent Technologies) and the assay was initiated.

The data was analyzed as follows: The non-mitochondrial respiration(Rot/AA) was subtracted from all oxygen consumption rate (OCR) values.Values of the individual well measurements for all three FCCP OCR fromBSA/PAL were divided by the average of the wells for each FCCP OCR valuefrom BSA. This ratio served as the amount of respiration that was theresult of palmitate oxidation. These numbers were then normalized to thevehicle average FCCP OCR value to generate the reported fold change inpalmitate oxidation.

Mitochondrial biogenesis: DMD human skeletal muscle cells were platedinto 96 well plates. Media was changed to Differentiation Medium andcells were allowed to differentiate for 7 days. On Day 4 ofdifferentiation, cells were either treated with vehicle, compound 2d, orinfected with PGC-1α adenovirus or LacZ adenovirus at a modality ofinfection of 200. Three days later cells were labeled withbromodeoxyuridine (BrdU) in culture media for 2 hours. Following theincubation, cells were washed, and then incubated with anti-BrdUantibody overnight at 4° C. The next day, samples were washed incubatedwith anti-mouse IgG HRP for 45 min at 37° C., and then washed. Opticaldensity was measured at 450 nM wavelength on a SpectraMax M5 (MolecularDevices).

Statistical Analysis: Data was analyzed in Graph Pad Prism. Normality ofdistribution was determined by D'Agostino-Pearson omnibus normalitytest. If the samples were normally distributed, they were analyzed byOne-Way ANOVA followed by a post hoc Dunnett's test vs DMSO controlcells or unpaired two tailed T-test. If the samples were not normallydistributed, then a Kruskal-Wallis test was used to determinesignificance. Results of statistical testing is demonstrated as follows:*p<0.05, **p<0.01, ***p<0.001, **** p<0.0001.

Results: Palmitate oxidation increased in a dose-dependent manner withcompound 2d (FIG. 1 ).

Mitochondrial biogenesis increased in a dose-dependent manner withCompound 2d treatment (FIG. 2 ). Overexpression of the transcriptionfactor PGC1a served as a positive control for the assay.

Example 4 Increasing Capacity for Endurance Exercise in Mouse Model ofDuchenne Muscular Dystrophy

Rationale: PPARδ is activated in response to exercise where it willelicit an increase in fatty acid utilization. Duchenne MuscularDystrophy is a progressive, early-onset degenerative muscle disease withassociated muscle function deficits resulting from the loss of theprotein dystrophin. Fatty acid metabolism and altered mitochondrialfunction are reported to be an aspect of the disease. In thisdemonstration, the mdx mouse model of Duchenne Muscular Dystrophy wastreated daily for 5 weeks with oral-administration of Compound 2d andtested for endurance exercise capacity by treadmill.

Animals and dosing: C57BL/10ScSn-Dmdmdx/J and C57BL/10ScSnJ mice ˜5-7weeks of age were received and housed singly in polycarbonate cages.Animals were fed standard chow and had access to feed and water at alltimes ad libitum. Compound 2d was formulated fresh each day for thisprotocol in the vehicle, 5% Ethanol+5% Solutol in purified water andtested at 10 or 30 mg per kg (mpk). Vehicle was dosed for controlgroups. All the animals were dosed by oral gavage (PO) for 34-35 days.The mice were dosed at 8 AM on the last in-life study day with thenecropsy started 2 hours after the final dose.

Endurance running assay: Mice were acclimated to a moving belt treadmillin a series of acclimation runs before evaluation for overall enduranceat a set maximal speed. Each mouse was run in a separate lane thatcontained an electric stimulating grid. The number of visits to theelectric stimulating grid and the number of shocks each animal receivedwere recorded by the instrument and a technician evaluated the animalduring the run to determine the time and distance to exhaustion. Themaximum speed for all the three endurance runs was capped at 20 m/min.The mice were considered exhausted if they stayed on the stimulationgrid with no limbs on the treadmill belt for more than 10 consecutiveseconds.

Statistical analysis: Values were tested for normality in all groups viaa D'Agostino-Pearson omnibus normality test and a Shapiro-Wilk normalitytest and tested by Kruskal-Wallis 1-Way ANOVA (non-parametric) followedby post hoc Dunn's multiple comparison testing versus the mdx vehiclegroup. Results of statistical testing is demonstrated as follows:*p<0.05, **p<0.01, ***p<0.001, **** p<0.0001.

Results: Dystrophic mdx mice consistently were outperformed by C57BL10mice in all three endurance runs. Compound 2d treated mdx miceconsistently demonstrated increased distance over mdx vehicle treatedgroup mice both in terms of total distance per run and when evaluatingaverage performance of the three runs (FIG. 3 ).

Example 5 Reducing Dystrophic Muscle Phenotype in Mouse Model ofDuchenne Muscular Dystrophy

Rationale: Similar to the muscle pathology in Duchenne MuscularDystrophy, mdx mice have dystrophic pathologies in skeletal muscle thatis apparent soon after birth. Key aspects of this phenotype evident bypathology are the loss of myofibers through apoptosis/necrosis, evidenceof regenerating muscle fibers, infiltrating immune cells, and increasedmuscle fibrosis. In this demonstration, mdx mice were administeredCompound 2d orally and assessed for muscle pathology.

Animals and dosing: Animals and dosing were as previously described. SeeExample 4.

Histology Pathology Assessment: Quadriceps, gastrocnemius and tibialisanterior muscles were harvested at necropsy, and fixed by immersion in10% neutral buffered formalin and embedded in paraffin. Tissues weresectioned at 5 μm from each block and slides were evaluated by a boardcertified veterinary pathologist. Histopathologic evaluation includedqualitative and semi-quantitative evaluation for myofiber necrosis,inflammation, myofiber regeneration and interstitial fibrosis, asoutlined in Tables 1, 2, and 3, respectively.

TABLE 1 Scoring criteria for myofiber necrosis/active regeneration ScoreDescription 0 None 0.5 Scant: scattered individual or very smallclusters of myofiber necrosis/regeneration, involving <3% of the section1 Minimal: scattered individual or small clusters of myofibernecrosis/regeneration, involving 3-10% of the section 2 Mild: morenoticeable, multifocal clusters of myofiber necrosis/regeneration,involving 11-30% of the section 3 Moderate: larger, coalescing foci ofmyofiber necrosis/regeneration, involving 31-50% of the section 4Marked: extensive foci of myofiber necrosis/regeneration, involving51-70% of the section 5 Severe: diffuse myofiber necrosis/regeneration,involving >70% of the section

TABLE 2 Scoring criteria for inflammation Score Description 0 None 0.5Scant: scattered inflammatory infiltrates, involving <3% of the section1 Minimal: scattered inflammatory infiltrates, involving 3-10% of thesection 2 Mild: more noticeable, multifocal clusters of inflammatoryinfiltrates, involving 11-30% of the section 3 Moderate: larger,coalescing foci of inflammatory infiltrates, involving 31-50% of thesection 4 Marked: extensive inflammatory cell infiltration, involving51-70% of the section 5 Severe: diffuse inflammatory cell infiltration,involving >70% of the section

TABLE 3 Scoring criteria for interstitial fibrosis Score Description 0None 0.5 Scant: scattered interstitial fibrosis, involving <3% of thesection 1 Minimal: scattered interstitial fibrosis, involving 3-10% ofthe section 2 Mild: more noticeable, multifocal areas of interstitialfibrosis, involving 11-30% of the section 3 Moderate: larger, coalescingfoci of interstitial fibrosis, involving 31-50% of the section 4 Marked:extensive interstitial fibrosis, involving 51-70% of the section 5Severe: diffuse interstitial fibrosis, involving >70% of the section

Immunofluorescent Assessment of Muscle Necrosis: Precut paraffin sectionslides were deparaffinized and incubated with AlexaFluor 488 conjugatedwheat germ agglutinin followed by an incubation with Alexa 568conjugated anti-mouse IgM (abcam, Product #ab175702). Slides were washedand mounted with coverslips using ProLong Diamond Antifade Mountant withDAPI. Imaging was performed on a Nikon fluorescent microscope using a40× objective and composite images were stitched together using NISElements Software, V4.4 (Nikon, Tokyo, Japan). Analysis was completedusing Image J 1.50b, Java 1.8.0_60 (64 bit).

Diaphragm Fibrosis: Diaphragm samples were harvested carefully and thecentral tendon was cut away to ensure hydroxyproline signal was derivedfrom muscle and not collagen-rich tendon. Hydroxyproline assay wasperformed according to the manufacturers' instructions (Sigma-AldrichHydroxyproline Assay Kit). Final values were calculated as follows:

$\frac{{ug}{hydroxyproline}}{{mg}{wet}{muscle}{wt}} = \frac{\begin{matrix}\left( {{ug}{HPL}{determined}{by}{standard}{curve} \times} \right. \\\left. \frac{{uL}{acid}{muscle}{was}{dissolved}{in}}{{uL}{supernatant}{assayed}} \right)\end{matrix}}{{mg}{of}{dissected}{muscle}}$

Statistical analysis: Diaphragm weights, histology scores andimmunofluorescence data were tested using a parametric test if normalitywas confirmed by Shapiro-Wilk normality test (unpaired t-test for 2groups or One way ANOVA followed by post hoc Dunn's multiple comparisontesting versus the mdx vehicle group for 3 groups) and a Mann-Whitneytest (2 groups) or Kruskal-Wallis One-Way ANOVA (non-parametric)followed by post hoc Dunn's multiple comparison testing versus the mdxvehicle group (3 groups) if the data were not normally distributed.Results of statistical testing is demonstrated as follows: *p<0.05,**p<0.01, ***p<0.001, **** p<0.0001.

Results: Total muscle damage was measured through qualitativehistological examination and quantitatively by immunofluorescentlabeling. Decreased necrosis was observed in the quadriceps muscle ofCompound 2d treated mdx mice (FIG. 4 ).

Quadriceps muscle sections were labeled fluorescently to detect IgMantibody accumulation within damaged myofibers, an indication of loss ofmyofiber integrity and active necrosis. Each muscle section was imagedin its entirety and the number and size of necrotic regions wasmeasured. Imaging was performed on a Nikon fluorescent microscope usinga 40× objective and composite images were stitched together using NISElements Software, V4.4 (Nikon, Tokyo, Japan). Analysis was completedusing Image J 1.50b, Java 1.8.0_60 (64 bit). The average size of thenecrotic regions was significantly reduced (FIG. 5 ).

Decreased inflammation was also observed, an indication of reducedmuscle damage, in Compound 2d treated mdx muscle (FIG. 6 ).

While the amount of muscle damage is decreased in Compound 2d treatedmdx mice, beneficial muscle regeneration increases with Compound 2d(FIG. 7 ).

DMD patients and the mdx model of DMD have impaired respiratory functiondue, in part, to fibrosis of the diaphragm. See Huang, P., et al.,Impaired respiratory function in mdx and mdx/utrn(+/−) mice. MuscleNerve, 2011. 43(2): p. 263-7. Fibrosis, replacement of muscle withfibrotic extracellular matrix, is a component of muscular dystrophy thatcontributes to overall muscle weakness and poor muscle regeneration.Repeated cycles of muscle degeneration and regeneration can contributeto the development of fibrosis. Compound 2d treatment reduced diaphragmnecrosis (FIG. 8 ), suggesting that fibrosis would also be reduced.

Diaphragms were evaluated for fibrosis by measuring hydroxyproline, anamino acid unique to collagen, in digested muscle. Mdx mice wereconfirmed to have increased fibrosis versus non-dystrophic control mice(FIG. 9 ).

Compound 2d administration reduced fibrosis in mdx diaphragms (FIG. 10).

Example 6 PPARδ Modulation after Ischemia Reperfusion Reduces KidneyInjury

Animals, surgery and dosing: Sprague-Dawley male rats approximately280-300 g, with ad libitum access to standard feed and water were usedin these experiments. Rats were anesthetized with isoflurane and placedventrally on a temperature controlled heated surgical platform. A skinincision was made on the dorsal surface, exposing both kidneys throughflank incisions. Vascular clips were applied to both renal pedicles andocclusion lasted 45 minutes. After 45 min, the clips were removed,kidneys were monitored for successful reperfusion, and surgical siteswere sutured. The sham group was subjected to similar surgicalprocedures, except that the occluding clamps were not applied. Fourindependent studies, testing each compound were performed. Compoundswere formulated as a fresh daily suspension in 0.25% sodiumcarboxymethyl-cellulose, 0.25% Tween-80 in purified water. Compoundswere dosed orally at 30 mg/kg 4 hours after animals awoke from surgeryand sham surgery and IRI control animals were similarly dosed withvehicle.

Blood collection and plasma creatinine measurement: Twenty-four (24)hours after reperfusion, blood was collected in K₂ EDTA tubes byretro-orbital bleeding from all groups under mild isoflurane anesthesia.Plasma was separated by centrifugation at 3000 rpm for 10 minutes at 4°C. Plasma creatinine was analyzed using a fully automated clinicalbiochemistry analyzer (Siemens Dimension® Xpand® Plus IntegratedChemistry System)

Data Analysis and Statistical Analysis:

GraphPad Prism software, Version 6.05 was used for graphing andstatistical testing.

Creatinine was tested for normal distribution in all groups via aD'Agostino-Pearson omnibus normality test and a Shapiro-Wilk normalitytest. Normally distributed data was subjected to an unpaired, two-tailedt test. Non-normally distributed data was subjected to a Mann-Whitneytest (non-parametric). Statistical significance is determined by p<0.05of IRI-vehicle compared to compound treated groups.

Results: PPARδ agonists, dosed 4 hours after ischemia, reduce kidneyinjury. Compound 2a (FIG. 11A), Compound 2d (FIG. 11B), and Compound 2n(FIG. 11C) reduce plasma creatinine when administered orally. The graphshows the plasma creatine levels in mg/dL in rats 24 hours after kidneyinjury reduce plasma creatinine when administered orally. The bars fromleft to right represent plasma creatine levels in rats with sham surgerydosed with 30 mpk vehicle; rats with acute kidney injury dosed with 30mpk vehicle; and rats with acute kidney injury dosed with 30 mpk ofCompound 2a (FIG. 11A), Compound 2d (FIG. 11B), and Compound 2n (FIG.11C).

1.-21. (canceled)
 22. A method of increasing endurance in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound having the structural formula:

or a pharmaceutically acceptable salt thereof.
 23. The method of claim22, wherein the subject has a muscle structure disorder, a musclefatigue disorder, a muscle mass disorder, or a mitochondrial disease.24. The method of claim 23, wherein: the muscle structure disorder isselected from Bethlem myopathy, central core disease, congenital fibertype disproportion, distal muscular dystrophy (MD), Duchenne MD, BeckerMD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline body myopathy,limb-girdle MD, a muscle sodium channel disorders, myotonicchondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline bodydisease, oculopharyngeal MD, or stress urinary incontinence; the musclefatigue disorder is selected from chronic fatigue syndrome, diabetes(type I or II), glycogen storage disease, fibromyalgia, Friedreich'sataxia, intermittent claudication, lipid storage myopathy, MELAS,mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy; the musclemass disorder is cachexia, cartilage degeneration, cerebral palsy,compartment syndrome, critical illness myopathy, inclusion bodymyositis, muscular atrophy (disuse), sarcopenia, steroid myopathy, orsystemic lupus erythematosus; and the mitochondrial disease is selectedfrom Alpers's Disease, CPEO-Chronic progressive externalophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary OpticNeuropathy (LHON), MELAS-Mitochondrial myopathy, encephalomyopathy,lactic acidosis, and stroke-like episodes, MERRF-Myoclonic epilepsy andragged-red fiber disease, NARP-neurogenic muscle weakness, ataxia, andretinitis pigmentosa, or Pearson Syndrome.
 25. The method of claim 22,wherein the subject has a mitochondrial disease selected from Alpers'sDisease, CPEO-Chronic progressive external ophthalmoplegia, Kearns-SayraSyndrome (KSS), Leber Hereditary Optic Neuropathy (LHON),MELAS-Mitochondrial myopathy, encephalomyopathy, lactic acidosis, andstroke-like episodes, MERRF-Myoclonic epilepsy and ragged-red fiberdisease, NARP-neurogenic muscle weakness, ataxia, and retinitispigmentosa, or Pearson Syndrome.
 26. The method of claim 22, wherein thesubject has Duchenne muscular dystrophy or Becker muscular dystrophy.